Process for the preparation of substituted tetralin and substituted indane derivatives

ABSTRACT

The present invention relates to novel processes for the preparation of substituted tetralin. and substituted indane derivatives. The present invention is further directed to novel processes for the preparation of intermediates in the preparation of the substituted tetralin and substituted indane derivatives.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/564,159, filed Apr. 21, 2004, which is incorporated by referenceherein.

FIELD OF THE INVENTION

The present invention relates to a novel processes for the preparationof substituted tetralin and substituted indane derivatives. Thesubstituted tetralin and substituted indane derivatives are PPAR alphaagonists, useful for elevating serum levels of high density lipoproteins(HDL), improving levels of intermediate density lipoproteins (IDL), andlowering serum levels of triglycerides, low density lipoproteins (LDL),atherogenic molecules, and/or free fatty acids (FFA). The substitutedtetralin and substituted indane compounds are further useful in treatinghypertriglyceridemia, raising levels of HDL, lowering levels of LDL,and/or lowering total cholesterol. The present invention is furtherdirected to novel processes for the preparation of intermediates in thepreparation of the substituted tetralin and substituted indanederivatives.

SUMMARY OF THE INVENTION

The present invention is directed to novel processes for the preparationof substituted tetralin and substituted indane derivatives. Thesubstituted tetralin and substituted indane derivatives and their usefor the treatment of PPAR alpha-mediated diseases including, but notlimited to dyslipidemia, cardiovascular disorders, impaired glucosetolerance, hyperinsulinemia, hyperglycemia, insulin resistance, early,intermediate or late Type II diabetes (NIDDM), complications thereofand/or Syndrome X are disclosed in U.S. patent application Ser. No.10/688,380, filed Oct. 17, 2003, U.S. patent application Ser. No.10/688,379, filed Oct. 17, 2003 and U.S. patent application Ser. No.10/688,572 filed Oct. 17, 2003, which are incorporated by referenceherein in their entirety.

The present invention is directed to a process for the preparation ofcompounds of formula (L)

wherein

-   -   Q is selected from the group consisting of OH, OPg², NH₂ and        N(Pg³Pg⁴); wherein Pg² is a carboxylic acid protecting group;        and wherein Pg³ and Pg⁴ are each independently selected from        hydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are        taken together with the nitrogen atom to which they are bound to        form C₃₋₁₀heteroaryl or C₃₋₁₀non-aromatic heterocyclic;    -   each of R₁ and R₂ is independently H, C₁₋₆alkyl,        (CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or        (CH₂)_(m)CO₂R₈;    -   wherein each of R_(a), R_(b), and R₈ is independently H or        C₁₋₆alkyl; and m is an integer from 1 to 6;    -   alternatively, R₁ and R₂ are taken together with the carbon atom        to which they are attached to form a C₃₋₇cycloalkyl;    -   n is an integer from 1 to 2;    -   X is S;    -   provided that when n is 1, X is bound at the 5 or 6 position;        and when n is 2, X is bound at the 6 or 7 position; provided        further that when n is 2 and X is bound at the 6 position, then        R³ is other than hydrogen and bound at the 7 position;    -   R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,        NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X;        provided that R₃ is other than CF₃;    -   each R₉ and R₁₀ is independently C₁₋₆alkyl;    -   R₄ is H or —(C₁₅straight chain alkylene)R₁₅; wherein R₁₅ is H,        C₁₋₇alkyl, [di(C₁₋₂alkyl)amino](C₁₋₆alkylene)—,        (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)—, C₁₋₆alkoxy, C₃₋₇alkenyl or        C₃₋₈alkynyl;    -   wherein R₄ has no more than 9 carbon atoms;    -   alternatively, R₄ is —(straight chain C₁₋₅alkylene)R₁₆; wherein        R₁₆ is C₃₋₆cycloalkyl or a 5-6 membered non-aromatic        heterocyclyl with between 1 and 2 heteroatoms selected from N,        O, and S;    -   wherein each of the above hydrocarbyl and heterocarbyl moieties        may be optionally substituted with between 1 and 3 substituents        independently selected from F, Cl, Br, I, amino, methyl, ethyl,        hydroxy or methoxy;    -   comprising        reacting a compound of formula (III), to yield the corresponding        compound of formula (IV), wherein Pg¹ is a nitrogen protecting        group which is inert to CISO₃H;        reacting the compound of formula (IV) with a suitably        substituted compound of formula (V) wherein R_(4a) is R₄ other        than hydrogen and wherein J is Br, Cl or l, in the presence of a        base, to yield the corresponding compound of formula (VI); and        then reacting the compound of formula (VI) with CISO₃H, to yield        the corresponding compound of formula (VII);    -   alternatively, reacting the compound of formula (IV) with        CISO₃H, to yield the corresponding compound of formula (VII)        wherein R₄ is hydrogen;        reacting the compound of formula (VII) with a reducing agent        capable of reducing the chlorosulfonyl group on the compound of        formula (VII), to yield a mixture of the corresponding compound        of formula (VIII) and the corresponding compound of formula        (IX);        reacting the compound of formula (VIII), isolated or in a        mixture with the compound of formula (IX), with a suitably        substituted compound of formula (X), wherein W is Br, Cl or l,        in the presence of a base, to yield the corresponding compound        of formula (XI);    -   alternatively, reacting the compound of formula (IX), isolated        or in a mixture with the compound of formula (VIII), with a        reducing agent capable of reducing the disulfide on compound of        formula (IX), to yield the corresponding compound of formula        (VIII); and then reacting the compound of formula (VIII) with a        suitably substituted compound of formula (X), wherein W is Br,        Cl or l, in the presence of a base, to yield the corresponding        compound of formula (XI);        reacting the compound of formula (XI), to yield the        corresponding compound of formula (L).

The present invention is further directed to a process for thepreparation of compounds of formula (L)

wherein

-   -   Q is selected from the group consisting of OH, OPg², NH₂ and        N(Pg³Pg⁴); wherein Pg² is a carboxylic acid protecting group;        and wherein Pg³ and Pg⁴ are each independently selected from        hydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are        taken together with the nitrogen atom to which they are bound to        form C₃₋₁₀heteroaryl or C₃₋₁₀non-aromatic heterocyclic;    -   each of R₁ and R₂ is independently H, C₁₋₆alkyl,        (CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or        (CH₂)_(m)CO₂R₈;    -   wherein each of R_(a), R_(b), and R₈ is independently H or        C₁₋₆alkyl; and m is an integer from 1 to 6;    -   alternatively, R₁ and R₂ are taken together with the carbon atom        to which they are attached to form a C₃₋₇cycloalkyl;    -   n is an integer from 1 to 2;    -   X is S;    -   provided that when n is 1, X is bound at the 5 or 6 position;        and when n is 2, X is bound at the 6 or 7 position; provided        further that when n is 2 and X is bound at the 6 position, then        R³ is other than hydrogen and bound at the 7 position;    -   R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,        NHCOR₁₀, CONHR₁₀, or COOR₁₀; and R₃ is ortho or meta to X;        provided that R₃ is other than CF₃;    -   each R₉ and R₁₀ is independently C₁₋₆alkyl;    -   R₄ is H or —(C₁₋₅straight chain alkylene)R₁₅; wherein R₁₅ is H,        C₁₋₇alkyl, [di(C₁₋₂alkyl)amino](C₁₋₆alkylene)—,        (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)—, C₁₋₆alkoxy, C₃₋₇alkenyl or        C₃₋₈alkynyl;    -   wherein R₄ has no more than 9 carbon atoms;    -   alternatively, R₄ is —(straight chain C₁₋₅alkylene)R₁₆; wherein        R₁₆ is C₃₋₆cycloalkyl or a 5-6 membered non-aromatic        heterocyclyl with between 1 and 2 heteroatoms selected from N,        O, and S;    -   wherein each of the above hydrocarbyl and heterocarbyl moieties        may be optionally substituted with between 1 and 3 substituents        independently selected from F, Cl, Br, I, amino, methyl, ethyl,        hydroxy or methoxy;    -   comprising        reacting a compound of formula (III), to yield the corresponding        compound of formula (IV), wherein Pg¹ is a nitrogen protecting        group which is inert to CISO₃H;        reacting the compound of formula (IV) with a suitably        substituted compound of formula (V) wherein R_(4a) is R₄ other        than hydrogen and wherein J is Br, Cl or I, in the presence of a        base, to yield the corresponding compound of formula (VI); and        then reacting the compound of formula (VI) with CISO₃H, to yield        the corresponding compound of formula (VII);    -   alternatively, reacting the compound of formula (IV) with        CISO₃H, to yield the corresponding compound of formula (VII)        wherein R⁴ is hydrogen;        reacting the compound of formula (VII) with a reducing agent        capable of reducing the chlorosulfonyl group on the compound of        formula (VII), to yield a mixture of the corresponding compound        of formula (VIII) and the corresponding compound of formula        (IX);        de-protecting the compound of formula (VIII), isolated or in a        mixture with the compound of formula (IX), to yield the        corresponding compound of formula (XIII);    -   alternatively, de-protecting the compound of formula (IX),        isolated or in a mixture with the compound of formula (VIII), to        yield a corresponding compound of formula (XII); and then        reducing the compound of formula (XII) with a reducing agent        capable of reducing the disulfide on compound of formula (XII),        to yield the corresponding compound of formula (XIII);    -   alternatively still, reacting the compound of formula (IX),        isolated or in a mixture with the compound of formula (VIII),        with a reducing agent capable of reducing the disulfide on        compound of formula (IX), to yield the corresponding compound of        formula (VIII); and then de-protecting the compound of formula        (VIII), to yield the corresponding compound of formula (XIII);        reacting the compound of (XIII) with a suitably substituted        compound of formula (X), wherein W is Br, Cl or I, in the        presence of a base, to yield the corresponding compound of        formula (L).

The present invention is further directed to a process for thepreparation of compounds of formula (L)

wherein

-   -   Q is selected from the group consisting of OH, OPg², NH₂ and        N(Pg³Pg⁴); wherein Pg² is a carboxylic acid protecting group;        and wherein Pg³ and Pg⁴ are each independently selected from        hydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are        taken together with the nitrogen atom to which they are bound to        form C₃₋₁₀heteroaryl or C₃₋₁₀non-aromatic heterocyclic;    -   each of R₁ and R₂ is independently H, C₁₋₆alkyl,        (CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or        (CH₂)_(m)CO₂R₈;    -   wherein each of R_(a), R_(b), and R₈ is independently H or        C₁₋₆alkyl; and m is an integer from 1 to 6;    -   alternatively, R₁ and R₂ are taken together with the carbon atom        to which they are attached to form a C₃₋₇cycloalkyl;    -   n is an integer from 1 to 2;    -   X is S;    -   provided that when n is 1, X is bound at the 5 or 6 position;        and when n is 2, X is bound at the 6 or 7 position; provided        further that when n is 2 and X is bound at the 6 position, then        R³ is other than hydrogen and bound at the 7 position;    -   R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,        NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X;        provided that R₃ is other than CF₃;    -   each R₉ and R₁₀ is independently C₁₋₆alkyl;    -   R₄ is —(C₁₋₅straight chain alkylene)R₁₅; wherein R₁₅ is H,        C₁₋₇alkyl, [di(C₁₋₂alkyl)amino](C₁₋₆alkylene)—,        (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)—, C₁₋₆alkoxy, C₃₋₇alkenyl or        C₃₋₈alkynyl;    -   wherein R₄ has no more than 9 carbon atoms;    -   alternatively, R₄ is —(straight chain C₁₋₅alkylene)R₁₆; wherein        R₁₆ is C₃₋₆cycloalkyl or a 5-6 membered non-aromatic        heterocyclyl with between 1 and 2 heteroatoms selected from N,        O, and S;    -   wherein each of the above hydrocarbyl and heterocarbyl moieties        may be optionally substituted with between 1 and 3 substituents        independently selected from F, Cl, Br, I, amino, methyl, ethyl,        hydroxy or methoxy;    -   comprising        reacting a compound of formula (III), to yield the corresponding        compound of formula (IV), wherein Pg¹ is a nitrogen protecting        group which is inert to CISO₃H;        reacting the compound of formula (IV) with CISO₃H, to yield the        corresponding compound of formula (VIIa);        reacting thecompound of formula (VIIa) with a reducing agent        capable of reducing the chlorosulfonyl group on the compound of        formula (VIIa), to yield a mixture of the corresponding compound        of formula (VIIIa) and the corresponding compound of formula        (IXa);        de-protecting the compound of formula (VIIIa), isolated or in a        mixture with the compound of formula (IXa), to yield the        corresponding compound of formula (XIIIa); and then reacting the        compound of formula (XIIIa) with a suitably substituted compound        of formula (X), wherein W is Cl, Br or I, in the presence of a        base, to yield the corresponding compound of formula (La);    -   alternatively, reacting the compound of formula (IXa), isolated        or in a mixture with the compound of formula (VIIIa), with a        reducing agent capable of reducing the disulfide on the compound        of formula (IXa), to yield the corresponding compound of formula        (VIIIa); then reacting the compound of formula (VIIIa) with a        suitably substituted compound of formula (X) wherein W is Br, Cl        or I, in the presence of a base, to yield the corresponding        compound of formula (XIa); and then reacting the compound of        formula (XIa), to yield the corresponding compound of formula        (La);    -   alternatively still, de-protecting the compound of formula        (IXa), isolated or in a mixture with the compound of formula        (VIIIa), to yield the corresponding compound of formula (XIIa);        then reacting the compound of formula (XIIa) with a reducing        agent capable of reducing the disulfide on the compound of        formula (XIIa), to yield the corresponding compound of formula        (XIIIa); and then reacting the compound of formula (XIIIa) with        a suitably substituted compound is of formula (X) wherein W is        Br, Cl or I, in the presence of a base, to yield the        corresponding compound of formula (La);        reacting the compound of formula (La) with a suitably        substituted compound of formula (V) wherein R_(4a) is R₄ other        than hydrogen and wherein J is Br, Cl or I, to yield the        corresponding compound of formula (Lb);    -   alternatively, reacting the compound of formula (La) with a        suitably substituted acylating agent capable of attaching an        —C(O)—R_(4b) group onto the nitrogen of the compound of formula        (La), wherein R_(4b) is selected from (C₁₋₄straight chain        alkylene)R₁₅ or (straight chain C₁₋₄alkylene)R₁₆, in the        presence of a base, to yield the corresponding compound of        formula (XVIII); and then reacting the compound of        formula (XVIII) with a reducing agent capable of reducing the        amide on the compound of formula (XVIII), to yield the        corresponding compound of formula (Lb).

The present invention is further directed to a process for thepreparation of compounds of formula (Lc)

wherein

-   -   Q is selected from the group consisting of OH, OPg², NH₂ and        N(Pg³Pg⁴); wherein Pg² is a carboxylic acid protecting group;        and wherein Pg³ and Pg⁴ are each independently selected from        hydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are        taken together with the nitrogen atom to which they are bound to        form C₃₋₁₀heteroaryl or C₃₋₁₀non-aromatic heterocyclic;    -   each of R₁ and R₂ is independently H, C₁₋₆alkyl,        (CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or        (CH₂)_(m)CO₂R₈;    -   wherein each of R_(a), R_(b), and R₈ is independently H or        C₁₋₆alkyl; and m is an integer from 1 to 6;    -   alternatively, R₁ and R₂ are taken together with the carbon atom        to which they are attached to form a C₃₋₇cycloalkyl;    -   n is an integer from 1 to 2;    -   X is S;    -   provided that when n is 1, X is bound at the 5 or 6 position;        and when n is 2, X is bound at the 6 or 7 position; provided        further that when n is 2 and X is bound at the 6 position, then        R³ is other than hydrogen and bound at the 7 position;    -   R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,        NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X;        provided that R₃ is other than CF₃;    -   each R₉ and R₁₀ is independently C₁₋₆alkyl;    -   R_(4b) is —(C₁₋₄straight chain alkylene)R₁₅; wherein R₁₅ is H,        C₁₋₇alkyl, [di(C₁₋₂alkyl)amino](C₁₋₆alkylene)—,        (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)—, C₁₋₆alkoxy, C₃₋₇alkenyl or        C₃₋₈alkynyl;    -   wherein R_(4b) has no more than 8 carbon atoms;    -   alternatively, R_(4b) is —(straight chain C₁₋₄alkylene)R₁₆;        wherein R₁₆ is C₃₋₆cycloalkyl or a 5-6 membered non-aromatic        heterocyclyl with between 1 and 2 heteroatoms selected from N,        O, and S;    -   wherein each of the above hydrocarbyl and heterocarbyl moieties        may be optionally substituted with between 1 and 3 substituents        independently selected from F, Cl, Br, I, amino, methyl, ethyl,        hydroxy or methoxy;    -   comprising        reacting a suitably substituted compound of formula (III) with a        suitably substituted acylating agent capable of attaching an        —C(O)—R_(4b) group onto the nitrogen of the compound of formula        (III), in the presence of a base, to yield the corresponding        compound of formula (XIV);        reacting the compound of formula (XIV) with CISO₃H, to yield the        corresponding compound of formula (XV);        reacting the compound of formula (XV) with a reducing agent        capable of reducing the chlorosulfonyl group on the compound of        formula (XV), to yield a mixture of the corresponding compound        of formula (XVI) and the corresponding compound of formula        (XVII);        reacting the compound of formula (XVI), isolated or in a mixture        with the compound of formula (XVII), with a reducing agent        capable of reducing the amide on the compound of formula (XVI),        to yield the corresponding compound of formula (XIIIb);    -   alternatively, reacting the compound of formula (XVII), isolated        or in a mixture with the compound of formula (XVI), with a        reducing agent capable of reducing the amide and the disulfide        on the compound of formula (XVII), to yield the corresponding        compound of formula (XIIIb);        reacting the compound of formula (XIIIb) with a suitably        substituted compound of formula (X) wherein W is Br, Cl or I, in        the presence of a base, to yield the corresponding compound of        formula (Lc).

The present invention is further directed to a process for thepreparation of a compound of formula (Lc)

wherein

-   -   Q is selected from the group consisting of OH, OPg², NH₂ and        N(Pg³Pg⁴); wherein Pg² is a carboxylic acid protecting group;        and wherein Pg³ and Pg⁴ are each independently selected from        hydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are        taken together with the nitrogen atom to which they are bound to        form C₃₋₁₀heteroaryl or C₃₋₁₀non-aromatic heterocyclic;    -   each of R₁ and R₂ is independently H, C₁₋₆alkyl,        (CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or        (CH₂)_(m)CO₂R₈;    -   wherein each of R_(a), R_(b), and R₈ is independently H or        C₁₋₆alkyl; and m is an integer from 1 to 6;    -   alternatively, R₁ and R₂ are taken together with the carbon atom        to which they are attached to form a C₃₋₇cycloalkyl;    -   n is an integer from 1 to 2;    -   X is S;    -   provided that when n is 1, X is bound at the 5 or 6 position;        and when n is 2, X is bound at the 6 or 7 position; provided        further that when n is 2 and X is bound at the 6 position, then        R³ is other than hydrogen and bound at the 7 position;    -   R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,        NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X;        provided that R₃ is other than CF₃;    -   each R₉ and R₁₀ is independently C₁₋₆alkyl;    -   R_(4b) is —(C₁₋₄straight chain alkylene)R₁₅; wherein R₁₅ is H,        C₁₋₇alkyl, [di(C₁₋₂alkyl)amino](C₁₋₆alkylene)—,        (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)—, C₁₋₆alkoxy, C₃₋₇alkenyl or        C₃₋₈alkynyl;    -   wherein R_(4b) has no more than 8 carbon atoms;    -   alternatively, R_(4b) is —(straight chain C₁₋₄alkylene)R₁₆;        wherein R₁₆ is C₃₋₆cycloalkyl or a 5-6 membered non-aromatic        heterocyclyl with between 1 and 2 heteroatoms selected from N,        O, and S;    -   wherein each of the above hydrocarbyl and heterocarbyl moieties        may be optionally substituted with between 1 and 3 substituents        independently selected from F, Cl, Br, I, amino, methyl, ethyl,        hydroxy or methoxy;    -   comprising        reacting a suitably substituted compound of formula (III) with a        suitably substituted acylating agent capable of attaching an        —C(O)—R_(4b) group onto the nitrogen of the compound of formula        (III), in the presence of a base, to yield the corresponding        compound of formula (XIV);        reacting the compound of formula (XIV) with CISO₃H, to yield the        corresponding compound of formula (XV);        reacting the compound of formula (XV) with a reducing agent        capable of reducing the chlorosulfonyl group and the amide group        on the compound of formula (XV), to yield the corresponding        compound of formula (XIIIb);        reacting the compound of formula (XIIIb) with a suitably        substituted compound of formula (X) wherein W is Br, Cl or I, in        the presence of a base, to yield the corresponding compound of        formula (Lc).

In an embodiment of the present invention is a process for thepreparation of a compound of formula (Ld)

wherein Q_(a) is OH or OPg², wherein Pg²is a carboxylic acid protectinggroup. In another embodiment of the present invention is a process forthe preparation of a compound of formula (Ld) wherein Q_(a) is OPg²wherein Pg² is a carboxylic acid protecting group.

The present invention is further directed to a novel process for thepreparation of a compound of formula (I)

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆ amide thereof,

-   -   wherein    -   each of R₁ and R₂ is independently H, C₁₋₆alkyl,        (CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or        (CH₂)_(m)CO₂R₈;    -   wherein each of R_(a), R_(b), and R₈ is independently H or        C₁₋₆alkyl; and m is an integer from 1 to 6;    -   alternatively, R₁ and R₂ are taken together with the carbon atom        to which they are attached to form a C₃₋₇cycloalkyl;    -   n is an integer from 1 to 2;    -   X is S;    -   provided that when n is 1, X is bound at the 5 or 6 position;        and when n is 2, X is bound at the 6 or 7 position; provided        further that when n is 2 and X is bound at the 6 position, then        R³ is other than hydrogen and bound at the 7 position;    -   R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,        NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X;        provided that R₃ is other than CF₃;    -   each R₉ and R₁₀ is independently C₁₋₆alkyl;    -   R₄ is H or —(C₁₋₅straight chain alkylene)R₁₅; wherein R₁₅ is H,        C₁₋₇alkyl, [di(C₁₋₂alkyl)amino](C₁₋₆alkylene)—,        (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)—, C₁₋₆alkoxy, C₃₋₇alkenyl or        C₃₋₈alkynyl;    -   wherein R₄ has no more than 9 carbon atoms;    -   alternatively, R₄ is —(straight chain C₁₋₅alkylene)R₁₆; wherein        R₁₆ is C₃₋₆cycloalkyl or a 5-6 membered non-aromatic        heterocyclyl with between 1 and 2 heteroatoms selected from N,        O, and S;    -   c is an integer from 0 to 1;    -   each of R₅ and R₇ is independently selected from H, C₁₋₆alkyl,        halo, cyano, nitro, COR₁₁, COOR₁₁, C₁₋₄alkoxy, C₁₋₄alkylthio,        hydroxy, phenyl, NR₁₁R₁₂ or a 5-6 membered heterocyclyl with        between 1 and 2 heteroatoms selected from N, O, and S;    -   R₆ is selected from C₁₋₆alkyl, halo, cyano, nitro, COR₁₃,        COOR₁₃, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, phenyl, NR₁₃R₁₄ or a        5-6 membered heterocyclyl with between 1 and 2 heteroatoms        selected from N, O, and S;    -   alternatively, R₅ and R₆ or R₆ and R₇ may be taken together to        be a bivalent moiety, saturated or unsaturated, selected from        C₃₋₄alkylene (for example, —(CH₂)₃— or —(CH₂)₄—), C₃₋₄alkenylene        (for example, —CH═CH—CH₂— or —CH═CH—CH═CH—) or        (CHI₁₋₂)_(p)N(CH₁₋₂)_(q);    -   p is an integer from 0 to 2 and q is an integer from 1 to 3;        wherein the sum (p+q) is at least 2;    -   each R₁₁, R₁₂, R₁₃ and R₁₄ is independently H or C₁₋₆alkyl;    -   wherein each of the above hydrocarbyl and heterocarbyl moieties        may be optionally substituted with between 1 and 3 substituents        independently selected from F, Cl, Br, I, amino, methyl, ethyl,        hydroxy or methoxy;    -   comprising    -   reacting a compound of formula (L), wherein Q is selected from        the group consisting of OH, OPg², NH₂ and N(Pg³Pg⁴); wherein Pg²        is a carboxylic acid protecting group; and wherein Pg³ and Pg⁴        are each independently selected from hydrogen, C₁₋₈alkyl,        C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are taken together with        the nitrogen atom to which they are bound to form        C₃₋₁₀heteroaryl or C₃₋₁₀non-aromatic heterocyclic; to yield the        corresponding compound of formula (I).

In an embodiment of the present invention is a process for thepreparation of a compound of formula (II)

also known as2-[[2-[ethyl[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]amino]-2,3-dihydro-1H-inden-5-yl]thio]-2-methyl-propanoicacid or2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionicacid.

In another embodiment of the present invention is a process for thepreparation of a compound of formula (IIa)

also known as2-[[(2R)-2-[ethyl[[[4-(trifluoromethoxy)phenyl]amino]carbonyl]amino]-2,3-dihydro-1H-inden-5-yl]thio]-2-methyl-propanoicacid or2-{(2R)-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionicacid.

The present invention is further directed to a process for thepreparation of the compound of formula (Le)

wherein Q_(b) is selected from the group consisting of C₁₋₆alkoxy,wherein the C₁₋₆alkoxy is not substituted with amino; comprising

(a) reacting a compound of formula (Ld) with(S)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, ata temperature in the range of from about 35° C. to about 0° C.; to yieldthe corresponding (R,S) diastereomeric salt, the compound of formula(XX);

(b) reacting the (R,S) diastereomeric salt, the compound of formula(XX), with an inorganic base, to yield the corresponding compound offormula (Le).

The present invention is further directed to a process for thepreparation of the compound of formula (Le)

wherein Q_(b) is selected from the group consisting of C₁₋₆alkoxy,wherein the C₁₋₆alkoxy is not substituted with amino; comprising

(a) reacting a compound of formula (Ld) with(R)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperaturegreater than about 35° C., preferably at a temperature greater thanabout 45° C.; or in THF at about room temperature, to yield thecorresponding (R,R) diastereomeric salt, the compound of formula (XXI).

(b) reacting the (R,R) diastereomeric salt, the compound of formula(XXI) with an inorganic base, to yield the corresponding compound offormula (Le).

The present invention is further directed to a process for thepreparation of the compound of formula (Lf)

wherein Q_(b) is selected from the group consisting of C₁₋₆alkoxy,wherein the C₁₋₆alkoxy is not substituted with amino; comprising

(a) reacting a compound of formula (Ld) with(S)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperaturegreater than about 35° C., preferably at a temperature greater thanabout 45° C.; or in THF at about room temperature; to yield thecorresponding (S,S) diastereomeric salt, the compound of formula (XXII).

(b) reacting the (S,S) diastereomeric salt, the compound of formula(XXI) with an inorganic base, to yield the corresponding compound offormula (Lf).

The present invention is further directed to a process for thepreparation of the compound of formula (Lf)

wherein Q_(b) is selected from the group consisting of C₁₋₆alkoxy,wherein the C₁₋₆alkoxy is not substituted with amino; comprising

(a) reacting a compound of formula (Ld) with(R)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, ata temperature in the range of from about 35° C. to about 0° C.; to yieldthe corresponding (S,R) diastereomeric salt, the compound of formula(XXIII);

(b) reacting the (S,R) diastereomeric salt, the compound of formula(XXIII) with an inorganic base, to yield the corresponding compound offormula (Lf).

The present invention is further directed to a novel crystalline salt ofthe compound of formula (IIa), more specifically, anN,N′-dibenzylethylenediamine (benzathine) salt of the compound offormula (IIa). The present invention is further directed to anN,N′-dibenzylethylenediamine salt of the compound of formula (IIa)wherein the ratio of the compound of formula (IIa) to theN,N′-dibenzylethylenediamine is 1:1. The present invention is furtherdirected to a process for the preparation of the benzathine salt of thecompound of formula (IIa).

The present invention is further directed to a compound preparedaccording to any of the processes described herein.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and a compound prepared accordingto any of the processes described herein. An illustration of theinvention is a pharmaceutical composition made by mixing a compoundprepared according to any of the processes described herein and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing acompound prepared according to any of the processes described herein anda pharmaceutically acceptable carrier.

In one embodiment, the pharmaceutical composition comprises thecompound:

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆ amide thereof.

In another embodiment, the pharmaceutical composition comprises thecompound:

Exemplifying the present invention are methods of treating a PPARalpha-mediated disease in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of acompound prepared according to any of the processes described herein ora pharmaceutical composition as described above. Further exemplifyingthe present invention are methods of elevating serum levels of highdensity lipoproteins (HDL), improving levels of intermediate densitylipoproteins (IDL), lowering serum levels of triglycerides, low densitylipbproteins (LDL), atherogenic molecules, and/or free fatty acids(FFA), treating hypertriglyceridemia, raising levels of HDL, loweringlevels of LDL, and/or lowering total cholesterol, in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of a compound prepared according to any of theprocesses described herein or a pharmaceutical composition as describedabove.

Further exemplifying the invention are methods for treatingdyslipidemia, cardiovascular disorders, impaired glucose tolerance,hyperinsulinemia, hyperglycemia, insulin resistance, early, intermediateor late Type II diabetes (NIDDM), complications thereof, or Syndrome X,in a subject in need thereof comprising administering to the subject atherapeutically effective amount of a compound prepared according to anyof the processes described herein or a pharmaceutical composition asdescribed above.

Further exemplifying the invention are methods for the treatment,prevention, or for inhibiting the progression of one or more of thefollowing conditions or diseases: phase I hyperlipidemia; pre-clinicalhyperlipidemia; phase II hyperlipidemia; hypertension; CAD (coronaryartery disease); coronary heart disease; hypertriglyceridemia; loweringserum levels of low-density lipoproteins (LDL), IDL, and/orsmall-density LDL and other atherogenic molecules, or molecules thatcause atherosclerotic complications, thereby reducing cardiovascularcomplications; elevating serum levels of high-density lipoproteins(HDL); lowering serum levels of triglycerides, LDL, and/or free fattyacids; and/or lowering FPG/HbA1c.

Another example of the invention is the use of a compound preparedaccording to any of the processes described herein in the preparation ofa medicament for treating (a) dyslipidemia, (b) cardiovasculardisorders, (c) impaired glucose tolerance, (d) hyperinsulinemia, (e)hyperglycemia, (f) insulin resistance, (g) early Type II diabetes(NIDDM), (h) intermediate Type II diabetes (NIDDM), (i) late Type IIdiabetes (NIDDM), (j) complications of Type II diabetes or (k) SyndromeX, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

“Alkyl” includes optionally substituted straight chain and branchedhydrocarbons with at least one hydrogen removed to form a radical group.Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl,octyl, and so on. As used herein, alkyl also includes cycloalkyl, suchas cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“Alkenyl” includes optionally substituted straight chain and branchedhydrocarbon radicals as above with at least one carbon-carbon doublebond (Sp²). Alkenyls include ethenyl (or vinyl), prop-1-enyl,prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl,but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein. As used herein,alkenyl also includes cycloalkenyl. Cis and trans or (E) and (Z) formsare included within the invention.

“Alkynyl” includes optionally substituted straight chain and branchedhydrocarbon radicals as above with at least one carbon-carbon triplebond (sp). Alkynyls include ethynyl, propynyls, butynyls, and pentynyls.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkynyl doesnot include cycloalkynyl.

“Alkoxy” includes an optionally substituted straight chain or branchedalkyl group with a terminal oxygen linking the alkyl group to the restof the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy,butoxy, t-butoxy, pentoxy and so on.

“Aminoalkyl”, “thioalkyl”, and “sulfonylalkyl” are analogous to alkoxy,replacing the terminal oxygen atom of alkoxy with, respectively, NH (orNR), S, and SO₂. Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl, andso on.

“Aryl” includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl,indenyl, and so on, any of which may be optionally substituted. Arylalso includes arylalkyl groups such as benzyl, phenethyl, andphenylpropyl. Aryl includes a ring system containing an optionallysubstituted 6-membered carbocyclic aromatic ring, said system may bebicyclic, bridge, and/or fused. The system may include rings that arearomatic, or partially or completely saturated. Examples of ring systemsinclude indenyl, pentalenyl, 1-4-dihydronaphthyl, indanyl,benzimidazolyl, benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl,and so on.

“Heterocyclyl” includes optionally substituted aromatic and nonaromaticrings having carbon atoms and at least one heteroatom (O, S, N) orheteroatom moiety (SO₂, CO, CONH, COO) in the ring. Unless otherwiseindicated, a heterocyclic radical may have a valence connecting it tothe rest of the molecule through a carbon atom, such as 3-furyl or2-imidazolyl, or through a heteroatom, such as N-piperidyl or1-pyrazolyl. Preferably a monocyclic heterocyclyl has between 5 and 7ring atoms, or between 5 and 6 ring atoms; there may be between 1 and 5heteroatoms or heteroatom moieties in the ring, and preferably between 1and 3, or between 1 and 2. A heterocyclyl may be saturated, unsaturated,aromatic (e.g., heteroaryl), nonaromatic, or fused.

Heterocyclyl also includes fused, e.g., bicyclic, rings, such as thoseoptionally condensed with an optionally substituted carbocyclic orheterocyclic five- or six-membered aromatic ring. For example,“heteroaryl” includes an optionally substituted six-memberedheteroaromatic ring containing 1, 2 or 3 nitrogen atoms condensed withan optionally substituted five- or six-membered carbocyclic orheterocyclic aromatic ring. Said heterocyclic five- or six-memberedaromatic ring condensed with the said five- or six-membered aromaticring may contain 1, 2 or 3 nitrogen atoms where it is a six-memberedring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfurwhere it is a five-membered ring.

Examples of heterocyclyls include thiazoylyl, furyl, thienyl, pyranyl,isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl,pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. Forexample, preferred heterocyclyls or heterocyclic radicals includemorpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino,thienyl,and more preferably, piperidyl or morpholinyl.

Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl,imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzothiazolyl.

“Acyl” refers to a carbonyl moiety attached to either a hydrogen atom(i.e., a formyl group) or to an optionally substituted alkyl or alkenylchain, or heterocyclyl.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo, andpreferably fluoro or chloro as a substituent on an alkyl group, with oneor more halo atoms, such as trifluoromethyl, trifluoromethoxy,trifluoromethylthio, difluoromethoxy, or fluoromethylthio.

“Alkanediyl” or “alkylene” represents straight or branched chainoptionally substituted bivalent alkane radicals such as, for example,methylene, ethylene, propylene, butylene, pentylene or hexylene.

“Alkenediyl” represents, analogous to the above, straight or branchedchain optionally substituted bivalent alkene radicals such as, forexample, propenylene, butenylene, pentenylene or hexenylene. In suchradicals, the carbon atom linking a nitrogen preferably should besaturated.

“Aroyl” refers to a carbonyl moiety attached to an optionallysubstituted aryl or heteroaryl group, wherein aryl and heteroaryl havethe definitions provided above. In particular, benzoyl isphenylcarbonyl.

As defined herein, two radicals, together with the atom(s) to which theyare attached may form an optionally substituted 4- to 7-, 5- to 7-, or a5- to 6-membered ring carbocyclic or heterocyclic ring, which ring maybe saturated, unsaturated or aromatic. Said rings may be as definedabove in the Summary of the Invention section.

“Enantiomer excess” or “ee”, usually expressed as a percentage,describes the excess of one enantiomer over the other. The percentageenantiomer excess, ee=100(Xr−Xs)/(Xr+Xs), where Xr>Xs. Alternatively,ee=100(2X-1), where X is the mole fraction of the dominant enantiomer inthe mixture. Please note that Xr and Xs represent the mole fraction of(R)-enantiomer and (S)-enantiomer respectively in the mixture.

“Pharmaceutically acceptable salts, esters, and amides” includecarboxylate salts, amino acid addition salts, esters, and amides whichare within a reasonable benefitrisk ratio, pharmacologically effectiveand suitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response. These salts, esters, andamides may be, for example, C₁₋₈alkyl, C₃₋₈cycloalkyl, aryl,C₂₋₁₀heteroaryl, or C₂₋₁₀non-aromatic heterocyclic salts, esters, andamides. Salts, free acids, and esters are more preferable than amides onthe terminal carboxylate/carboxylic acid group on the left of formula(I). Representative salts include hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate,glucoheptonate, lactiobionate, and laurylsulfonate. These may includealkali metal and alkali earth cations such as sodium, potassium,calcium, and magnesium, as well as non-toxic ammonium, quaternaryammonium, and amine cations such as tetramethyl ammonium, methylamine,trimethylamine, and ethylamine. See example, S. M. Berge, et al.,“Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66:1-19 which isincorporated herein by reference. Representative pharmaceuticallyacceptable amides of the invention include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocyclic or heteroaromatic ringmoieties containing at least one nitrogen atom and optionally between 1and 2 additional heteroatoms. Preferred amides are derived from ammonia,C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Representativepharmaceutically acceptable esters of the invention include C₁₋₇ alkyl,C₅₋₇cycloalkyl, phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred estersinclude methyl and ethyl esters.

As used herein, all hydrocarbon radicals, whether saturated, unsaturatedor aromatic, and whether or not cyclic, straight chain, or branched, andalso similarly with all heterocyclic radicals, eachradical includessubstituted radicals is of that type and monovalent, bivalent, andmultivalent radicals as indicated by the context. The context willindicate that the substituent is an alkylene or hydrocarbon radical withat least two hydrogen atoms removed (bivalent) or more hydrogen atomsremoved (multivalent).

Radicals or structure fragments as defined herein are understood toinclude substituted radicals or structure fragments. Hydrocarbylsinclude monovalent radicals containing carbon and hydrogen such asalkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl (whether aromaticor unsaturated), as well as corresponding bivalent (or multi-valent)radicals such as alkylene, alkenylene, phenylene, and so on.Heterocarbyls include monovalent and bivalent (or multi-valent) radicalscontaining carbon, optionally hydrogen, and at least one heteroatom.Examples of monovalent heterocarbyls include acyl, acyloxy, alkoxyacyl,heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl,and so on. Using “alkyl” as an example, “alkyl” should be understood toinclude substituted alkyl having one or more substitutions, such asbetween 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents maybe the same (dihydroxy, dimethyl) or different (chlorofluoro-,chlorobenzyl- or aminomethyl-substituted). Examples of substituted alkylinclude haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl,perchloromethyl, 2-bromoethyl, trifluoromethyl, and 3-iodocyclopentyl),hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl),aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and2-aminopropyl), alkylalkyl, and so on. A di(C₁₋₆alkyl)amino groupincludes independently selected alkyl groups, to form, for example,methylpropylamino and isopropylmethylamino, in addition dialkylaminogroups having two of the same alkyl group such as dimethylamino ordiethylamino.

Only stable compounds are intended. For example, where there is anNR₁₁R₁₂ group, and R can be an alkenyl group, the double bond is atleast one carbon removed from the nitrogen to avoid enamine formation.Similarly, where —(CH₂)_(p)—N—(CH₂)_(q)— can be unsaturated, theappropriate hydrogen atom(s) is(are) included or omitted, as shown in—(CH₂)—N═(CH)—(CH₂)— or —(CH₂)—NH—(CH)═(CH)—.

Unless otherwise noted, when naming substituents such as X and R³, thefollowing numbering of the indane and tetralin, respectively, will beapplied.

As used herein, unless otherwise noted, the term “aprotic solvent” shallmean any solvent that does not yield a proton. Suitable examplesinclude, but are not limited to DMF, dioxane, THF, acetonitrile,pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Grouis in Organic Synthesis, John Wiley & Sons, 1991.

As used herein, unless otherwise noted, the term “carboxylic acidprotecting group” shall mean a group which may be attached to —C(O)O—portion of the carboxylic acid to protect said carboxylic acid fromparticipating in a reaction and which may be readily removed followingthe reaction. Suitable carboxylic acid protecting groups include, butare not limited C₁₋₇alkyl, C₅₋₇Cycloalkyl, phenyl, phenylC₁₋₆alkyl, andthe like. Other suitable carboxylic acid protecting groups may be foundin texts such as T. W. Greene & P. G. M. Wuts, Protective Groups inOrganic Synthesis, John Wiley & Sons, 1991.

In the process for the preparation of the compounds of formula (I),application of the present invention to a mixture of enantiomers of thecompound of formula (L), substantially free of the S enantiomer, willresult in the production of a mixture of enantiomers of formula (I),substantially free of the S enantiomer. Similarly, in the process forthe preparation of the compounds of formula (I), application of thepresent invention to a mixture of enantiomers of formula (L),substantially free of the R enantiomer, will result in the production ofa mixture of enantiomers of formula (I), substantially free of the Renantiomer. Preferably, the enantiomeric excess of the desiredenantiomer of formula (I) is at least about 90% ee, more preferably, atleast about 96% ee, most preferably, about 99% ee.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, followed by fractional crystallization and regeneration ofthe free base. The compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary. Alternatively, the compounds may beresolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

When a particular group is “substituted” (e.g., phenyl, aryl, aralkyl,heteroaryl), that group may have one or more substituents, preferablyfrom one to three substituents, more preferably from one to twosubstituents, independently selected from the list of substituents.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means that15 amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows: Ac = Acetyl (i.e. —C(O)—CH₃) ACN or MeCN =Acetonitrile Alloc = CH₂═CHCH₂—O—C(O)— DCE = Dichloroethane DCM =Dichloromethane DIPEA or DIEA = Diisopropylethylamine DMA =Dimethylacetamide DMF = N,N-Dimethytformamide DMSO = Dimethyl sulfoxide% ee = Percent Enantiomeric Excess Et₃N or TEA = Triethylamine EtOAc =Ethyl acetate EtOH = Ethanol FTIR = Fourier Transform Infra-Red HPLC =High Pressure Liquid Chromatography iPrOAc = Isopropyl acetate KF =Karl-Fisher (% water measurement) LAH = Lithium Aluminum Hydride LDA =Lithium Diisopropylamide LHMDS = Lithium bis(trimethylsilyl)amide MeOH =Methanol mp = Melting Point MS = Mass Spectroscopy MTBE = Methyl-t-butylether MTr = 2,3,6-trimethyl-4-methoxy-phenyl-sulfonyl NMR = NuclearMagnetic Resonance Pd(PPh₃)₄ = Palladium (0)Tetrakis(triphenylphosphine) TFA = Trifluoroacetic Acid THF =Tetrahydrofuran

In an embodiment of the present invention, in the compound of formula(I), (a) one of R₁ and R₂ is methyl or ethyl; (b) each of R₁ and R₂ ismethyl; (c) R₁ and R₂ taken together are cyclobutyl or cyclopentyl; (d)R₃ is H; (e) R₄ is H or C₂₋₇alkyl; (e) R₄ is H or C₂₋₅alkyl; (f) R₄ isethyl; (g) R₄ is H; (h) n is 1; (i) 2; (j) at least one of R₅ and R₇ isH; (k) R₆ is C₁₋₄alkyl, halomethoxy, or halothiomethoxy (i.e—S-(halomethyl)); (I) R₆ is t-butyl, isopropyl, trifluoromethyl,trifluoromethoxy, trifluorothiomethoxy (i.e. —S—CF₃), difluoromethoxy,or dimethylamino; (m) R₃ is H, R₄ is C₂₋₇alkyl; (n) R₄ is C₂₋₅alkyl; (o)R₆ is cyclopropylmethyl, isopropyl, isobutyl, methylethylamino, ordiethylamino; (p) the (S) enantiomer at the C-2 position on the indaneor tetralin; (q) the (R) entantiomer at the. C-2 position on the indaneor tetralin; (r) where R₁₅ is C₁₋₇ alkyl,[di(C₁₋₂alkyl)amino](C₁₋₆alkylene), (C₁₋₃alkoxyacyl)(C₁₋₆alkylene),C₁₋₆alkoxy, C₃₋₇alkenyl, or C₃₋₈alkynyl; (s) R₆ is trifluoromethylthioor trifluoromethoxy; or (t) any combination of the above.

In another embodiment of the present invention, the compound of formula(I) selected from the group consisting of2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionicacid;2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3fluoro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionicacid;2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-chloro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionicacid; 2-{6-[1-Ethyl-3-(4-ylsulfanyl}-2-methylpropionic acid;2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5,6,7,8tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid;2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-trifluoromethoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionicacid;2-{6-[1-Ethyl-3-(4-hydroxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionicacid;2-{6-[(4-Aminophenyl)-1-ethyl-ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionicacid and2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-4-trifluoromethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionicacid.

In another embodiment of the present invention the compound of formula(I) selected from the group consisting of 2-{6-[1-Ethyl-3-(4-methylpropionic acid;2-{6-[3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionicacid;2-{2-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionicacid;2-{2-[1-Ethyl-3-(4-trifluoromethylsulfanylphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionicacid; and2-Methyl-2-{2-[1-propyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}propionicacid.

In an embodiment of the present invention c is 0. In another embodimentof the present invention n is 1 and X is bound at the 5-position. In yetanother embodiment of the present invention n is 2 and X is bound at the6- or 7-position, preferably at the 6-position.

In an embodiment of the present invention, wherein n is 1 and R₃ ishydrogen or is other than hydrogen and is bound at the 4-, 6- or7-position, then the —X—C(R₁R₂)—C(O)-Q group is bound at the 5-position.In another embodiment of the present invention, wherein n is 1 and R₃ ishydrogen or is other than hydrogen and is bound at the 4-, 6- or 7-position, then the —X—C(R₁R₂)—C(O)—OH group is bound at the 5-position.

In an embodiment of the present invention, wherein n is 1 and R₃ isother than hydrogen and is bound at the 5-position, then the—X—C(R₁R₂)—C(O)-Q group is bound at the 6-position. In anotherembodiment of the present invention, wherein n is 1 and R₃ is other thanhydrogen and is bound at the 5-position, then the —X—C(R₁R₂)—C(O)—OHgroup is bound at the 6-position.

In an embodiment of the present invention Q is Opg² or N(Pg³Pg⁴),wherein Pg² is a carboxylic acid protecting group as readily understoodby one skilled in the art, including, but not limited to, C₁₋₇alkyl,C₅₋₇cycloalkyl, phenyl, phenylC₁₋₆alkyl, and the like; and Pg³ and Pg⁴are each independently selected from hydrogen, C₁₋₈alkyl, C₃₋₈cycloalkylor aryl; alternatively Pg³ and Pg⁴ are taken together with the nitrogenatom to which they are bound to form C₃ ioheteroaryl orC₃₋₁₀non-aromatic heterocyclic, preferably a 5- or 6-memberedheterocyclic or heteroaromatic ring moiety containing at least onenitrogen atom and optionally between 1 and 2 additional heteroatoms. Inanother embodiment of the present invention Q is OPg², wherein Pg² is acarboxylic acid protecting group.

In an embodiment of the present invention Q is selected from the groupconsisting of hydroxy, unsubstituted C₁₋₆alkoxy, amino, unsubstitutedC₁₋₄alkylamino and di(unsubstitutedC₁₋₄alkyl)amino. In anotherembodiment of the present invention Q is selected from the groupconsisting of hydroxy, methoxy, ethoxy, ispropyloxy, n-butyloxy,t-butoxy, amino, methylamino and dimethylamino. In yet anotherembodiment of the present invention Q is C₁₋₆alkoxy, wherein theC₁₋₆alkoxy is not substituted with amino. In yet another embodiment ofthe present invention, Q is selected from the group consisting ofmethoxy, ethoxy and t-butoxy.

The present invention is directed to a process for the preparation ofcompounds of formula (L)

wherein Q, X, R₁, R₂, R₃, n and R₄ are as herein defined. The compoundsof formula (L) are useful as intermediates in the preparation ofcompounds of formula (I).

Compounds of formula (L) may be prepared according to the processoutlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (III), a knowncompound or compound prepared by known methods, is reacted (for example,protected) according to known methods, to yield the correspondingcompound of formula (IV), wherein Pg₁ is a nitrogen protecting groupwhich is inert to CISO₃H, such as, Alloc (CH₂═CHCH₂—O—C(O)—), acetyl(CH₃—C(O)—), (C₁₄alkyl)-C(O)—, and the like. For example, the compoundof formula (III) is reacted with a suitably selected protecting reagentsuch as Alloc-Cl (CH₂═CHCH₂—O—C(O)—Cl), Alloc₂O(CH₂═CHCH₂—OC(O)—O—C(O)O—CH₂CH═CH₂), AcCl (CH₃—C(O)—Cl), Ac₂O(CH₃—C(O)—O—C(O)—CH₃), and the like. Wherein the compound of formula(III) is reacted with a Alloc-Cl, or Alloc₂O, the correspondingprotecting group Pg₁ is Alloc. Preferably, Pg₁ is selected from Alloc oracetyl.

The compound of formula (IV) is reacted with a suitable substitutedcompound of formula (V), wherein R_(4a) is R₄ other than hydrogen andwherein J is Br, Cl, or I, a known compound or compound prepared byknown methods, in the presence of a base such as NaH, n-butyl lithium,LDA, LHMDS, and the like, in a polar aprotic solvent such as THF,dioxane, MTBE, and the like, to yield the corresponding compound offormula (VI). The compound of formula (VI) is then reacted with ClSO₃H,optionally in a polar organic solvent which is inert to ClSO₃H, such asDCM, DCE, acetonitrile, DMF, to yield the corresponding compound offormula (VII).

Alternatively, the compound of formula (IV) is reacted with ClSO₃H,optionally in a polar organic solvent which is inert to ClSO₃H, such asDCM, DCE, acetonitrile, DMF, to yield the corresponding compound offormula (VII) wherein R₄ is hydrogen.

The compound of formula (VII) is reacted with a reducing agent capableof reducing the chlorosulfonyl group on the compound of formula (VII),such as Zn, and the like, in the presence of an acid such as HCl, H₂SO₄,and the like, in an aprotic solvent such as acetonitrile, THF, dioxane,and the like; or with Zn in the presence of (CH₃)₂SiCl₂ and DMA, in anaprotic organic solvent such as THF, dioxane, acetonitrile,1,2-dichloroethane, and the like; to yield a mixture of thecorresponding compound of formula (VIII) and the corresponding compoundof formula (IX).

Alternatively, wherein the compound of formula (VII) Pg₁ is tosyl orMTr, the compound of formula (VII) is reacted with a reducing agentcapable of reducing the chlorosulfonyl group on the compound of formula(VII), such as LiAlH₄, and the like, in an organic solvent which isinert to the reducing agent, such as THF, dioxane, and the like, at atemperature in the range of from about room temperature to about reflux,preferably at about reflux, to yield the corresponding compound offormula (VIII).

The compound of formula (VIII), isolated or in a mixture with thecompound of formula (IX) is reacted with a suitably substituted compoundof formula (X), wherein W is Br, Cl or I, a known compound or compoundprepared by known methods, in the presence of an organic base which isinert to the compound of formula (X), such as TEA, DIPEA, pyridine, andthe like or in the presence of an inorganic base which is inert to thecompound of formula (X), such as NaHCO₃, Na₂CO₃, K₂CO₃, Cs₂CO₃, and thelike, in a polar aprotic solvent such as THF, dioxane, DMF,acetonitrile, and the like, to yield the corresponding compound offormula (XI).

Alternatively, the compound of formula (IX), isolated or in a mixturewith the compound of formula (VIII) is reacted with a reducing agentwhich is is capable of reducing the disulfide on the compound of formula(VIII), such as LiAlH₄, LiBH₄, NaBH₄, and the like, in an organicsolvent which is inert to the reducing agent, such as THF, dioxane, andthe like, at a temperature in the range of from about room temperatureto about reflux, preferably at about room temperature, to yield thecorresponding compound of formula (VIII), which is preferably notisolated. The compound of formula (VIII) is then reacted with a suitablysubstituted compound of formula (X), wherein W is Br, Cl or I, a knowncompound or compound prepared by known methods, in the presence of anorganic base which is inert to the compound of formula (X), such as TEA,DIPEA, pyridine, and the like or in the presence of an inorganic basewhich is inert to the compound of formula (X), such as NaHCO₃, Na₂CO₃,K₂CO₃, Cs₂CO₃, and the like, in a polar aprotic solvent such as THF,dioxane, DMF, acetonitrile, and the like, to yield the correspondingcompound of formula (XI).

The compound of formula (XI) is reacted to yield the correspondingcompound of formula (L). For example, the compound of formula (XI) isde-protected according to known methods, such as those described inProtective Groups in Organic Chemistry, ed. J. F. W. McOmie, PlenunPressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups inOrganic Synthesis, John Wiley & Sons, 1991, to yield the correspondingcompound of formula (L).

Compounds of formula (L) may alternatively be prepared according to theprocess outlined in Scheme 2.

Accordingly, a suitably substituted compound of formula (III), a knowncompound or compound prepared by known methods, is reacted (for example,protected) according to known methods, to yield the correspondingcompound of formula (IV), wherein Pg₁ is a nitrogen protecting groupwhich is inert to ClSO₃H, such as, Alloc (CH₂═CHCH₂—O—C(O)—), acetyl(CH₃—C(O)—), (C₁₋₄alkyl)-C(O)—, and the like. For example, the compoundof formula (III) is reacted with a suitably selected protecting reagentsuch as Alloc-Cl (CH₂═CHCH₂—O—C(O)—Cl), Alloc₂O.(CH₂═CHCH₂—OC(O)—O—C(O)O—CH₂CH═CH₂), AcCl (CH₃—C(O)—Cl), Ac₂O.(CH₃—C(O)—O—C(O)—CH₃), and the like. Wherein the compound of formula(III) is reacted with a Alloc-Cl, or Alloc₂O, the correspondingprotecting group Pg₁ is Alloc. Preferably, Pg₁ is selected from Alloc oracetyl.

The compound of formula (IV) is reacted with a suitable substitutedcompound of formula (V), wherein R_(4a) is R₄ other than hydrogen andwherein J is Br, Cl, or I, a known compound or compound prepared byknown methods, in the presence of a base such as NaH, n-butyl lithium,LDA, LHMDS, and the like, in a polar aprotic solvent such as THF,dioxane, MTBE, and the like, to yield the corresponding compound offormula (VI). The compound of formula (VI) is then reacted with ClSO₃H,optionally in a polar organic solvent which is inert to ClSO₃H, such asDCM, DCE, acetonitrile, DMF, to yield the corresponding compound offormula (VII).

Alternatively, the compound of formula (IV) is reacted with ClSO₃H,optionally in a polar organic solvent which is inert to ClSO₃H, such asDCM, DCE, acetonitrile, DMF, to yield the corresponding compound offormula (VII) wherein R₄ is hydrogen.

The compound of formula (VII) is reacted with a reducing agent capableof reducing the chlorosulfonyl group on the compound of formula (VII),such as Zn, and the like, in the presence of an acid such as HCl, H₂SO₄,and the like, in an aprotic solvent such as acetonitrile, THF, dioxane,and the like; or with Zn in the presence of (CH₃)₂SiC₁₋₂ and DMA, in anaprotic organic solvent such as THF, dioxane, acetonitrile,1,2-dichloroethane, and the like; to yield a mixture of thecorresponding compound of formula (VIII) and the corresponding compoundof formula (IX).

Alternatively, wherein the compound of formula (VII) Pg₁ is tosyl orMTr, the compound of formula (VII) is reacted with a reducing agentcapable of reducing the chlorosulfonyl group on the compound of formula(VII), such as LiAlH₄, and the like, in an organic solvent which isinert to the reducing agent, such as THF, dioxane, and the like, at atemperature in the range of from about room temperature to about reflux,preferably at about reflux, to yield the corresponding compound offormula (VIII).

The compound of formula (VIII), isolated or in a mixture with thecompound of formula (IX), is de-protected according to known methods,such as those described in Protective Groucs in Organic Chemistry, ed.J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts,Protective Grouis in Organic Synthesis, John Wiley & Sons, 1991, toyield the corresponding compound of formula (XIII).

Alternatively, the compound of formula (IX), isolated or in a mixturewith the compound of formula (VIII), is reacted with a reducing agentwhich is capable of reducing the disulfide on the compound of formula(IX), such as LiAlH₄, LiBH₄, NaBH₄, and the like, in an organic solventwhich is inert to the reducing agent, such as THF, dioxane, and thelike, at a temperature in the range of from about room temperature toabout reflux, preferably at about room temperature, to yield thecorresponding compound of formula (VIII), which is preferably notisolated. The compound of formula (VIII) is then de-protected accordingto known methods, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W.Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991, to yield the corresponding compound of formula(XIII).

Alternatively still, the compound of formula (IX), isolated or in amixture with the compound of formula (VIII), is de-protected accordingto known methods, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W.Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991, to yield the corresponding compound of formula(XII). The compound of formula (XII) is then reacted with a reducingagent which is capable of reducing the disulfide on the compound offormula (XII), such as LiAlH₄, LiBH₄, NaBH₄, and the like, in an organicsolvent which is inert to the reducing agent, such as THF, dioxane, andthe like, at a temperature in the range of from about room temperatureto about reflux, preferably at about room temperature, to yield thecorresponding compound of formula (XIII).

The compound of formula (XIII) reacted with a suitably substitutedcompound of formula (X), wherein W is Br, Cl or I, a known compound orcompound prepared by known methods, in the presence of an organic basewhich is inert to the compound of formula (X), such as TEA, DIPEA,pyridine, and the like or in the presence of an inorganic base which isinert to the compound of formula (X), such as NaHCO₃, Na₂CO₃, K₂CO₃,Cs₂CO₃, and the like, in a polar aprotic solvent such as THF, dioxane,DMF, acetonitrile, and the like, to yield the corresponding compound offormula (L).

Compounds of formula (L) wherein R₄ is other than hydrogen mayalternatively be prepared according to the process outlined in Scheme 3.

Accordingly, a suitably substituted compound of formula (III), a knowncompound or compound prepared by known methods, is reacted (for example,protected) according to known methods, to yield the correspondingcompound of formula (IV), wherein Pg₁ is a nitrogen protecting groupwhich is inert to ClSO₃H, such as, Alloc (CH₂═CHCH₂—O—C(O)—), acetyl(CH₃—C(O)—), (C₁₋₄alkyl)-C(O)—, and the like. For example, the compoundof formula (III) is reacted with a suitably selected protecting reagentsuch as Alloc-Cl (CH₂═CHCH₂-Q-C(O)—Cl), Alloc₂O.(CH₂═CHCH₂—OC(O)—O—C(O)O—CH₂CH═CH₂), AcCl (CH₃—C(O)—Cl), Ac₂O.(CH₃—C(O)—O—C(O)—CH₃), and the like. Wherein the compound of formula(III) is reacted with a Alloc-Cl, or Alloc₂O, the correspondingprotecting group Pg₁ is Alloc. Preferably, Pg₁ is selected from Alloc oracetyl.

The compound of formula (IV) is reacted with ClSO₃H, optionally in apolar organic solvent which is inert to ClSO₃H, such as DCM, DCE,acetonitrile, DMF, to yield the corresponding compound of formula (VIIa)(i.e. the corresponding compound of formula (VII) wherein R⁴ ishydrogen.).

The compound of formula (VIIIa) is reacted with a reducing agent capableof reducing the chlorosulfonyl group on the compound of formula (VIIa)such as Zn, and the like, in the presence of an acid such as HCl, H₂SO₄,and the like, in an aprotic solvent such as acetonitrile, THF, dioxane,and the like; or with Zn in the presence of (CH₃)₂SiC₁₋₂ and DMA, in anaprotic organic solvent such as THF, dioxane, acetonitrile,1,2-dichloroethane, and the like; to yield a mixture of thecorresponding compound of formula (VIIIa) (i.e. the correspondingcompound of formula (VIII) wherein R⁴ is hydrogen) and the correspondingcompound of formula (IXa) (i.e. the corresponding compound of formula(IXa) wherein R₄ is hydrogen).

The compound of formula (VIIIa), isolated or in a mixture with thecompound of formula (IXa) is de-protected according to known methods,such as those described in Protective Groups in Organic Chemistry, ed.J. F. W. McOmie, Plenun Pressm 1973 and T. W. Green and P. G. M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, toyield the corresponding compound of formula (XIIIa) (i.e. thecorresponding compound of formula (XIII) wherein R₄ is hydrogen). Thecompound of formula (XIIIa) is reacted with a suitably substitutedcompound of formula (X), wherein W is Br, Cl or I, a known compound orcompound prepared by known methods, in the presence of an organic basewhich is inert to the compound of formula (X), such as TEA, DIPEA,pyridine, and the like or in the presence of an inorganic base which isinert to the compound of formula (X), NaHCO₃, Na₂CO₃, K₂CO₃, Cs₂CO₃, andthe like, in a polar aprotic solvent such as THF, dioxane, DMF,acetonitrile, and the like, to yield the corresponding compound offormula (La) (i.e. the corresponding compound of formula (L) wherein R₄is hydrogen).

Alternatively, the compound of formula (IXa), isolated or in a mixturewith the compound of formula (VIIIa), is reacted with a reducing agentwhich is capable of reducing the disulfide on the compound of formula(IXa), such as LiAlH₄, LiBH₄, NaBH₄, and the like, in an organic solventwhich is inert to the reducing agent, such as THF, dioxane, and thelike, at a temperature in the range of from about room temperature toabout reflux, preferably at about room temperature, to yield thecorresponding compound of formula (VIIIa). The compound of formula(VIIIa) is then reacted with a suitably substituted compound of formula(X), wherein W is Br, Cl or I, a known compound or compound prepared byknown methods, in the presence of an organic base which is inert to thecompound of formula (X), such as TEA, DIPEA, pyridine, and the like orin the presence of an inorganic base which is inert to the compound offormula (X), NaHCO₃, Na₂CO₃, K₂CO₃, Cs₂CO₃, and the like, in a polaraprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like,to yield the corresponding compound of formula (XIa) (i.e. thecorresponding compound of formula (XI) wherein R₄ is hydrogen). Thecompound of formula (XIa) is then reacted to yield the correspondingcompound of formula (La). For example, the compound of formula (XIa) isde-protected according to known methods, such as those described inProtective Groups in Organic Chemistry, ed. J. F. W. McOmie, PlenunPressm 1973 and T. W. Green and P. G. M. Wuts, Protective Groups inOrganic Synthesis, John Wiley & Sons, 1991, to yield the correspondingcompound of formula (La).

Alternatively still, the compound of formula (IXa), isolated or in amixture with the compound of formula (VIIIa), is de-protected accordingto known methods, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenun Pressm 1973 and T. W.Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991, to yield the corresponding compound of formula(XIIa) (i.e. the corresponding compound of formula (XII) wherein R₄ ishydrogen). The compound of formula (XIIa) is then reacted with areducing agent which is capable of reducing the disulfide on thecompound of formula (XIIa), such as LiAlH₄, LiBH₄, NaBH₄, and the like,in an organic solvent which is inert to the reducing agent, such as THF,dioxane, and the like, at a temperature in the range of from about roomtemperature to about reflux, preferably at about room temperature, toyield the corresponding compound of formula (XIIIa) (i.e. thecorresponding compound of formula (XIII) wherein R₄ is hydrogen). Thecompound of formula (XIIIa) is then reacted with a suitably substitutedcompound of formula (X), wherein W is Br, Cl or I, a known compound orcompound prepared by known methods, in the presence of an organic basewhich is inert to the compound of formula (X), such as TEA, DIPEA,pyridine, and the like or in the presence of an inorganic base which isinert to the compound of formula (X), such as NaHCO₃, Na₂CO₃, K₂CO₃,Cs₂CO₃, and the like, in a polar aprotic solvent such as THF, dioxane,DMF, acetonitrile, and the like, to yield the corresponding compound offormula (La).

The compound of formula (La) is reacted with a suitably substitutedcompound of formula (V), wherein R_(4a) is R₄ other than hydrogen andwherein J is Br, Cl, or I, a known compound or compound prepared byknown methods, in the presence of a base such as NaH, n-butyl lithium,LDA, LHMDS, and the like, in a polar aprotic solvent such as THF,dioxane, MTBE, and the like, to yield the corresponding compound offormula (Lb). Alternatively, the compound of formula (La) is reactedwith a suitably substituted acylating agent capable of attaching an—C(O)—R_(4b) group onto the nitrogen of the compound of formula (La),wherein R_(4b) is selected from (C₁₋₄ straight chain alkylene)R₁₅ or(straight chain C₁₋₄alkylene)R₁₆, in the presence of an organic such asTEA, DIPEA, pyridine, and the like, or in the presence of an inorganicbase such as NaHCO₃, Na₂CO₃, K₂CO₃, Cs₂CO₃, and the like, in a polaraprotic solvent such as THF, dioxane, DMF, acetonitrile, and the like,to yield the corresponding compound of formula (XVIII); the compound offormula (XVIII) is then reacted with a reducing agent capable ofreducing the amide on the compound of formula (XVIII), such as borane,and the like, in a aprotic organic solvent such as THF, dioxane, MTBE,and the like, to yield the corresponding compound of formula (Lb).

Compounds of formula (L) wherein R₄ is other than hydrogen, (C₁ straightchain alkylene)R₁₅ or (straight chain C₁alkylene)R₁₆ may be preparedaccording to the process outlined in Scheme 4.

Accordingly, a suitably substituted compound of formula (III), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted acylating capable of attaching an —C(O)O—R_(4b)group onto the nitrogen of the compound of formula (III), wherein R_(4b)is selected from (C₁₄ straight chain alkylene)R₁₅ or (straight chain C₁₄alkylene)R₁₆, for example an acid chloride of the formulaCl—C(O)—R_(4b), a symmetric anhydride of the formulaR_(4b)—C(O)—O—C(O)—R_(4b), and the like, in the presence of an organicbase, preferably a tertiary amine base such as TEA, DIPEA, pyridine, andthe like, in an aprotic solvent such as THF, DMF, dioxane, ethylacetate, and the like; or in the presence of an organic or inorganicbase such as NaOH, KOH, Na₂CO₃, NaHCO₃, K₂CO₃, KHCO₃, TEA, DIPEA,pyridine, and the like, in a mixture of an aprotic solvent and water, toyield the corresponding compound of formula (XIV).

The compound of formula (XIV) is reacted with ClSO₃H, optionally in apolar organic solvent which is inert to ClSO₃H, such as DCM, DCE,acetonitrile, DMF, to yield the corresponding compound of formula (XV).

The compound of formula (XV) is reacted with a reducing agent capable ofreducing the chlorosulfonyl group on the compound of formula (XV), suchas Zn, and the like, in the presence of an acid such as HCl, H₂SO₄, andthe like, optionally in an aprotic solvent such as acetonitrile, THF,dioxane, and the like; or with Zn in the presence of (CH₃)₂SiC₁₋₂ andDMA, in an aprotic organic solvent such as THF, dioxane, acetonitrile,1,2-dichloroethane, and the like; to yield a mixture of the compound offormula (XVI) and the compound of formula (XVII).

One skilled in the art will recognize that when the compound of formula(XV) is reacted with a reducing agent capable of reducing thechlorosulfonyl group and the amide group on the compound of formula(XV), such as LiAlH₄, and the like, in an organic solvent which is inertto the reducing agent, such as THF, dioxane, and the like, at atemperature in the range of from about room temperature to about reflux,preferably at about reflux, then the compound of formula (XV) is reactedto yield the corresponding compound of formula (XIIIb) in one step.

The compound of formula (XVI), isolated or in a mixture with thecompound of formula (XVII) is reacted with a reducing agent which iscapable of reducing the amide on the compound of formula (XVI), such asLiAlH₄, borane, and the like, in an aprotic solvent which is inert tothe reducing agent, such as THF, dioxane, and the like, to yield thecorresponding compound of formula (XIIIb) (i.e. the correspondingcompound of formula (XIII) wherein R₄ is other than hydrogen). Whereinthe reducing agent is LiAlH₄, the compound(s) is reduced at atemperature in the range of from about room temperature to about reflux,preferably at about room temperature.

Alternatively, the compound of formula (XVII), isolated or in a mixturewith the compound of formula (XVI) is reacted with a reducing agentwhich is capable of reducing the amide on the compound of formula (XVII)and the disulfide on the compound of formula (XVII), such as LiAlH₄,borane, and the like, in an aprotic solvent which is inert to thereducing agent, such as THF, dioxane, and the like, to yield thecorresponding compound of formula (XIIIb). Wherein the reducing agent isLiAlH₄, the compound(s) is reduced at a temperature in the range of fromabout room temperature to about reflux, preferably at about roomtemperature.

The compound of formula (XIIIb) is reacted with a suitably substitutedcompound of formula (X), wherein W is Br, Cl or I, a known compound orcompound prepared by known methods, in the presence of an organic basewhich is inert to the compound of formula (X), such as TEA, DIPEA,pyridine, and the like or in the presence of an inorganic base which isinert to the compound of formula (X), such as NaHCO₃, Na₂CO₃, K₂CO₃,Cs₂CO₃, and the like, in a polar aprotic solvent such as THF, dioxane,DMF, acetonitrile, methanol, ethanol, and the like, to yield thecorresponding compound of formula (Lc) (i.e. the corresponding compoundof formula (L) wherein R₄ is selected from (C₂₋₅ straight chainalkylene)R₁₅ or (straight chain C₂₋₅ alkylene)R₁₆).

The present invention is further directed to a process for thepreparation of compounds of formula (I)

wherein R₁, R₂, X, R₃, n, R₄, c, R₅, R₆ and R₇ are as herein defined.The compounds of formula (I) are useful as PPAR alpha agonists, morespecifically as selective PPAR alpha agonists. PPAR alpha agonists areuseful for the treatment, prevention, or inhibiting the progression ofone or more of the following conditions or diseases: phase Ihyperlipidemia; pre-clinical hyperlipidemia; phase II hyperlipidemia;hypertension; CAD (coronary artery disease); coronary heart disease;hypertriglyceridemia; lowering serum levels of low-density lipoproteins(LDL), IDL, and/or small-density LDL and other atherogenic molecules, ormolecules that cause atherosclerotic complications, thereby reducingcardiovascular complications; elevating serum levels of high-densitylipoproteins (HDL); lowering serum levels of triglycerides, LDL, and/orfree fatty acids; and/or lowering FPG/HbA1c.

More specifically, the compound of formula (I) may be prepared byreacting a suitably substituted compound of formula (L) with a suitablysubstituted isocyanate, a compound of the formula (XIX)

according to known methods. One skilled in the art will recognize thatin reacting the compound of formula (L) with a suitably substitutedisocyanate, a compound of formula (XIX), it may be necessary ordesirable to protect reactive groups on the compound of formula (L),according to known methods. For example, it may be necessary ordesirable to protect the carboxylic acid or amide on the compound offormula (L) when Q is OH or NH₂, respectively. One skilled in the artwill further recognize that wherein the compound of formula (L) Q isOPg², NH or N(Pg³Pg⁴), the compound of formula (L) is reacted with asuitably substituted isocyanate, a compound of formula (XIX), accordingto known methods, to yield an intermediate which is then de-protectedaccording to known methods to yield the corresponding compound offormula (I).

In an embodiment of the present invention is a process for thepreparation of a compound of formula (L) wherein X is S, R₁ is methyl,R₂ is methyl, Q is OH or OPg², the —X—C(R₁R₂)—C(O)-Q is bound at the 5-position, R₃ is hydrogen, n is 1 and R₄ is ethyl. In another embodimentof the present invention is a process for the preparation of a compoundof formula (L) wherein X is S, R₁ is methyl, R₂ is methyl, Q is OPg²,Pg²is t-butyl, the —X—C(R₁R₂)—C(O)-Q is bound at the 5- position, R₃ ishydrogen, n is 1 and R₄ is ethyl.

In another embodiment of the present invention is a process for thepreparation of a compound of formula (I) or a pharmaceuticallyacceptable salt, C₁₋₆ester or C₁₋₆amide thereof, wherein X is S, R₁ ismethyl, R₂ is methyl, wherein —X—C(R₁R₂)—C(O)—OH is bound at the 5-position, R₃ is hydrogen, n is 1, R₄ is ethyl, c is 0, R₅ is hydrogen,R₆ is trifluoromethoxy and R₇ is hydrogen.

The present invention is further directed to a process for thepreparation of the compound of formula (Le)

wherein Q_(b) is selected from the group consisting of C₁₋₆alkoxy,wherein the C₁₋₆alkoxy is not substituted with amino. Preferably, Q_(b)is unsubstituted C₁₋₆alkoxy, more preferably, Q_(b) is selected from thegroup consisting of methoxy, ethoxy and t-butoxy.

More specifically, the compound of formula (Le) may be preparedaccording to the process outlined in Scheme 5.

Accordingly, a compound of formula (Ld) is reacted with(S)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol such as methanol,ethanol, and the like, preferably ethanol; or in acetone, at atemperature in the range of from about 35° C. to about 0° C., to yieldthe corresponding (R,S) diastereomeric salt, the compound of formula(XX).

The (R,S) diastereomeric salt, the compound of formula (XX), is r eactedwith an inorganic base such as NaOH, KOH, Na₂CO₃, K₂CO₃, and the like toyield the corresponding compound of formula (Le).

Preferably, the compound of formula (Le) is prepared with anenantiomeric excess in the range of from about 70 % ee to about 90 % ee.One skilled in the art will recognize that wherein a greater % ee isdesired, the diasteromeric salt of the compound of formula (Le) may befurther re-slurrried in or recrystallized from an organic solvent suchas methanol, ethanol, acetone, and the like.

The compound of formula (Le) may alternatively be prepared according tothe process outlined in Scheme 6.

Accordingly, a compound of formula (Ld) is reacted with(R)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperaturegreater than about 35° C., preferably at a temperature greater thanabout 45° C.; or in THF at about room temperature; to yield thecorresponding (R,R) diastereomeric salt, the compound of formula (XXI).

The (R,R) diastereomeric salt, the compound of formula (XXI), is reactedwith an inorganic base such as NaOH, KOH, Na₂CO₃, K₂CO₃, and the like toyield the corresponding compound of formula (Le).

Preferably, the compound of formula (Le) is prepared with anenantiomeric excess in the range of from about 70 % ee to about 90 % ee.One skilled in the art will recognize that wherein a greater % ee isdesired, the diasteromeric salt of the compound of formula (Le) may befurther re-slurrried in or recrystallized from an organic solvent suchas methanol, ethanol, acetone, and the like.

One skilled in the art will further recognize that the S-enantiomer ofthe compound of formula (Ld), a compound of formula (Lf)

may be similarly prepared by reacting a compound of formula (Ld) with(R)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol such as methanol,ethanol, and the like, preferably ethanol; or in acetone, at atemperature in the range of from about 35° C. to about 0° C.; to yieldthe corresponding (S,R) diastereomeric salt which is then reacted withan inorganic base such as NaOH, KOH, Na₂CO₃, K₂CO₃, and the like, toyield the corresponding compound of formula (Lf).

Alternatively, the S-enantiomer of the compound of formula (Ld) (i.e.the compound of formula (Lf)) may be prepared by reacting a compound offormula (Ld) with (S)-2-(4-hydroxyphenoxy)propionic acid, in acetone, ata temperature greater than about 35° C., preferably at a temperaturegreater than about 45° C.; or in THF at about room temperature; to yieldthe corresponding (S,S) diastereomeric salt which is then reacted withan inorganic base such as NaOH, KOH, Na₂CO₃, K₂CO₃, and the like, toyield the corresponding compound of formula (Lf).

The present invention is further directed to a novel crystalline salt ofthe compound of formula (IIa)

more specifically a crystalline N,N′-dibenzylethylenediamine(benzathine) salt of the compound of formula (IIa). In an embodiment ofthe present invention is a crystalline N.N′-dibenzylethylenediamine saltof the compound of formula (IIa) wherein the ratio of the compound offormula (IIa) to the N,N′-dibenzylethylenediamine is 1:1.

The crystalline benzathine salt of the compound of formula (IIa) may becharacterized by the major peaks of its X-ray diffraction peaks, aslisted in Table 1, below. The X-ray diffraction pattern was measured asfollows. The crystalline benzathine salt of the compound of formula(IIa) was backloaded into a conventional X-ray holder. Using anX-Celerator detector, the sample was scanned from 3 to 35 °2θ at a stepsize of 0.0165 °2θ and a time per step of 10.16 seconds. The effectivescan speed was 0.2067°/s. Instrument voltage and current settings of 45kV and 40 mA were employed. TABLE 1 XRD - Compound of formula (IIa)Benzathine Salt Position [°2θ] d-spacing [Å] Relative Intensity [%]6.3894 13.8336 17.39 8.0423 10.9938 13.38 12.157 7.2803 19.22 16.0125.5354 15.74 17.929 4.9475 20.77 18.048 4.9151 14.20 19.038 4.6618100.00 19.2656 4.6072 26.28 20.325 4.3694 10.65 21.943 4.0508 16.8522.190 4.0063 18.63 22.330 3.9815 12.37

The present invention is further directed to a process for thepreparation of the benzathine salt of the compound of formula (IIa).More particularly, the compound of formula (lha) is reacted withN,N′-dibenzylethylenediamine, in an aprotic solvent such as isopropylacetate, ethyl acetate, MTBE, and the like, preferably in isopropylacetate, preferably, at a temperature less than about 5° C., morepreferably, at a temperature in the range of from about 5° C. to about−5° C., yield the corresponding N,N′-dibenzylethylenediame (benzathine)salt of the compound of formula (IIa).

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

EXAMPLE 1 N-Indan-2-yl-acetamide

To a cooled mixture of 2-aminoindan (1.2 mol, 160.00 g) in ethyl acetate(1019 mL) at about 5-7° C. was added a solution of Na₂CO₃ (2.4 mol,254.65 g) in water (1528 mL) while stirring, followed by the addition ofa solution of acetyl chloride (1.32 mol, 109.19 g) slowly over 2 hours.The reaction temperature was maintained below 10° C. by adjusting theaddition rate. During the addition, a suspension was formed. After theaddition of acetyl chloride, the mixture was stirred at the roomtemperature for 1 hour. The precipitated solid was collected by vacuumfiltration and the filter cake was washed with water (200 mL), EtOAc(200 mL), and air-dried for 48 hours. The first crop of the product wasobtained as a white crystalline solid.

The filtrate was placed in a separatory funnel and the aqueous layer wasseparated. The organic layer was washed once with water (500 mL) andonce with brine (500 mL). The ethyl acetate layer was evaporated invacuo to half of its original volume and then diluted with heptane (1000mL) while stirring to produce a white suspension. The solid wascollected by vacuum filtration and washed twice with portions of heptane(300 mL). The second crop of the product was obtained as whitecrystalline solid.

mp 127-129° C.

¹H NMR (300 MHz, CDCl₃) δ 7.13 (m, 4H), 6.99 (br d, 1H), 4.57 (m, 1H),3.19 (dd, J ═16.1, 7.3 Hz, 2H), 2.78 (dd, J=16.0, 5.1 Hz, 2H), 1.85 (s,3H).

¹³C NMR (300 MHz, CDCl₃) δ 170.7, 141.4, 127.01, 125.1, 51.0, 41.2,23.5.

MS (ESI): m/z 176.2 (MH⁺).

Elemental Analysis for C₁₁H₁₃NO:

Calculated: C, 75.40; H, 7.48; N, 7.99

Found: C, 75.13; H, 7.73; N, 7.96.

EXAMPLE 2 2-Acetylamino-indan-5-sulfonyl chloride

To a 2 L 3-necked glass reaction flask equipped with stirrer, condenser,thermocouple, 500 mL addition funnel and nitrogen inlet was addedN-acetyl-2-aminoindan (0.96 mol, 167.70 g) and acetonitrile (490 mL).The reaction mixture was stirred and cooled in an ice-bath to about 3-5°C. and ClSO₃H (3.83 mol, 440 g) was added slowly. The first 30% of thereagent was added over 30 minutes while maintaining the reactiontemperature below 15° C. The ice-bath was then removed and the reactionmixture was warmed to room temperature. The remaining 70% of the reagentwas added over 30 minutes and the temperature of the reaction solutionrose to 80° C. at the end of the addition. The yellow reaction solutionwas stirred at 50° C. for about 20 hours. The reaction solution wascooled to 30° C. and slowly poured into a vigorously stirred mixture ofice (1620 g), water (945 mL), and acetonitrile (135 mL) in an ice-bathover about 10-15 minutes. The temperature of the quenching mixturedropped from 5° C. to −6° C. A white solid precipitated and the mixturewas stirred at about 0-5° C. for 30 minutes. The solid was collected byvacuum filtration and slurried 4 times with a cold mixture of water(4×300 mL). The pH of the last slurry was around 2-3. The solid was thenslurried with cold acetone (300 mL) (5-7° C.), collected by filtration,and finally rinsed with of cold acetone (200 mL). The solid product wasair-dried for 4 hours, followed by drying in a vacuum oven at roomtemperature for 48 hours. The product was obtained as a white solid.

mp 158-160° C.

¹H NMR (300 MHz, DMSO-d⁶) δ 8.53 (br s, 1H), 7.45 (s, 1H), 7.44 (d,J=7.8 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 4.45 (br m, 1H), 3.15 (m, 2H),2.77 (dd, J=16.2, 5.7 Hz, 2H), 1.85 (s, 3H).

¹³C NMR (300 MHz, DMSO-d⁶) δ 169.6, 145.3, 142.3, 140.9, 123.9, 123.7,121.6, 50.2, 38.6, 38.4, 22.2.

MS (ESI): m/z 274.0 (MH⁺)

Elemental Analysis for C₁₁H₁₂ClNO₃S.0.1H₂O:

Calculated: C, 47.95; H, 4.47; Cl, 12.87; N, 5.09; S, 11.64; KF, 0.66%

Found: C, 47.61; H, 4.49; Cl, 12.50; N, 5.13; S, 11.50; KF, 0.67%

EXAMPLE 3 N-(5-Mercapto-indan-2-yl)-acetamide

A suspension of zinc (22.94 g, 0.35 mol) and2-acetylamino-indan-5-sulfonyl chloride (93% weight) (29.45 g, 0.10 mol)in acetonitrile (200 mL) in a 1 Liter four-necked round-bottomed flaskequipped with a condenser, a thermometer, an addition funnel, and amechanical stirrer was heated to about 50-60° C. The heating source wasremoved and to the warm suspension was added concentrated HCl (59.20 g,0.60 mol) slowly over 1 hour. The addition rate was adjusted to maintainthe reaction temperature between about 70-75° C. A gentle gas (H₂)evolution was observed throughout the addition of HCl. The reaction wasthen cooled to about 30-36° C. over 30 minutes while stirring. Thereaction mixture was filtered into a 500 mL one-necked round-bottomedflask through a frited glass funnel to remove the Zn residue. Thereaction flask was rinsed with EtOAc (25 mL). The mixture wasconcentrated on a rotavapor under reduced pressure at about 45-50° C.bath temperature to remove most of the organic solvents. Theconcentrated aqueous solution was mixed with of EtOAc (150 mL), followedby the addition of H₂O. (75 mL). After stirring for 15 minutes, thelayers were separated. The organic layer was washed four times with H₂O.(3×75 mL). After separation of layers, the organic layer wasconcentrated on a rotavapor at 60° C. to ¼ of its original volume (about40 mL). Most of the precipitated white solid was dissolved by heating toreflux. The mixture was then diluted with MTBE (75 mL). The mixture wasstirred at ambient temperature for 18 hours. The solid product wascollected by vacuum filtration, washed with MTBE (20 mL), dried undernitrogen for 4 hours, then in a vacuum oven at about 40-45° C. for 24 h.The product was obtained as an off-white solid.

mp 128-129.5° C.

¹H NMR (300 MHz, DMSO-d⁶) δ 8.12 (br d, J=6.6 Hz, 1H), 7.15 (s, 1H),7.08 (brs, 2H), 5.18 (s, 1H), 4.41 (m, 1H), 3.09 (m, 2H), 2.69 (m, 2H),1.79 (s, 3H).

¹³C NMR (300 MHz, DMSO-d⁶) δ 168.9, 142.4, 138.2, 129.2, 126.6,125.0,124.8, 49.9, 38.9, 38.5, 22.5.

MS (ESI): m/z 208.2 (MH⁺)

Elemental Analysis for C₁₁H₁₃NOS:

Calculated: C, 63.73; H, 6.32; N, 6.76; S, 15.47

Found: C, 63.48; H, 6.50; N, 6.64; S, 15.56

EXAMPLE 4N-[5-(2-Acetylamino-indan-5-yldisulfanyl)-indan-2-yl]-acetamide

To a suspension of zinc (28.60 g, 0.44 mol) and2-acetylamino-indan-5-sulfonyl chloride (40.00 g, 0.146 mol) inacetonitrile (400 mL) in a three-necked round-bottomed flask equippedwith a magnetic stirrer, an addition funnel, and a thermometer was addeda solution of dichlorodimethylsilane (44.2 mL, 0.365 mol) inacetonitrile (50 mL) at room temperature over 1 hour. The reactiontemperature increased to 66° C. during the addition. After addition, thereaction mixture was stirred at room temperature for 20 hours and somesolids were formed.

THF (100 mL) was added to dissolve the suspension and the excess Zn wasremoved by decantation and rinsed with THF (20 mL. The crude ACN/THFsolution was extracted with heptane (3×300 mL) to remove the silanebyproducts. The ACN/THF layer was concentrated and re-dissolved in EtOAc(300 mL) and H₂O (150 mL). The mixture was stirred for 10 minutes andthe layers were separated. The organic layer was washed with H₂O. (2×200mL), brine (200 mL), and then concentrated to the half of its originalvolume. The solution was diluted with toluene (200 mL) and concentratedagain to remove all EtOAc. The suspension in toluene was warmed to 90°C. for 15 minutes and stirred at room temperature for 20 hours. Thesolid product was collected by vacuum filtration, rinsed with toluene(20 mL), air-dried for 2 hours, and further dried in a vacuum oven at60° C. for 2 days. The product was obtained as an off-white solid.

mp 165-168° C. (soften at 137° C.)

¹H NMR (300 MHz, DMSO-d⁶) δ 8.13 (d, J=7.7 Hz, 2H), 7.38 (s, 2H), 7.30(d, J=7.9 Hz, 2H), 7.22 (d, J=7.7 Hz, 2H), 4.42 (br m, 2H), 3.15 (m,2H), 3.11 (m, 2H), 2.71 (dd, J=16.2, 5.3 Hz, 4H), 1.78 (s, 6H).

¹³C NMR (300 MHz, DMSO-d⁶) δ 168.8, 142.9, 141.4, 133.7, 126.1, 125.3,124.0, 49.9, 38.9, 38.6, 22.5.

MS (ESI): m/z 413.1 (MH⁺)

EXAMPLE 5 tert-Butyl2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate

N-(5-Mercapto-indan-2-yl)-acetamide (330.0 g, 1.59 mol) was dissolved ina warm THF (1.65 L) at 50° C. The solution was then slowly added to LAHsolution (1 M in THF) (2.385 L, 2.385 mol) at about 60-66° C. over 25minutes to allow gentle reflux and slow gas evolution. After addition,the light yellow suspension was stirred under reflux for 4 hours. Thereaction was cooled to about 5-7° C. in an ice-water bath. The reactionwas quenched by the slow addition of methanol (203.7 g, 6.36 mol) undera nitrogen atmosphere and the reaction temperature was maintained below25° C. by adjusting the addition rate. After quenching, the resultedgreen suspension was cooled to 5-7° C. and treated with tert-butyl2-bromo-2-methylpropionate (354.7 g, 1.59 mol). The resulted mixture waswarmed to room temperature while stirring and then maintained withstirring at room temperature for 2 hours. The reaction mixture wastreated by the slow addition of H₂O. (90.6 mL) and 15% of aqueous NaOH(90.6 mL) sequentially. The resulted granular solid was removed byvacuum filtration through a 3L coarse frit funnel lined with Celitefilter aid. The filter cake was rinsed twice with THF (2×500 mL). Thecombined filtrate was concentrated in vacuo to remove about 70-80% ofTHF. The filter cake was suspended in EtOAc (2 L) and stirred for 30minutes. The suspension was filtered through a 3L coarse frit funnel.The filtrate was combined with the crude concentrated THF solutionobtained above. The combined organic layer was washed with H₂O. (2 L).After separation of layers, the organic layer was concentrated in vacuoat 50° C. to remove the most of volatiles. The concentrated solution wasdiluted with anhydrous ethanol (800 mL) and re-concentrated to yield apurple oil. The crude product was used for the next step without furtherpurification.

MS (ESI): m/z 336.1 (MH⁺)

EXAMPLE 6 (S)-2-(4-hvdroxyphenoxy)propionic acid

To (R)-2-chloropropionic acid (200 g, 1.81 mol) was added a solution of50% NaOH (147.4 g, 1.84 mol) in water (520 mL) with the internaltemperature below 25° C. In another flask, water (800 mL) andhydroquinone (811.8 g, 7.38 mol) were mixed. To the water/hydroquinonemixture was added 50% NaOH (1179.6 g, 14.71 mol), then the above(R)-2-chloropropionate sodium salt solution was added to the mixture,keeping the internal temperature below 55° C. The reaction mixture washeated at about 55-60° C. for an additional 2 h.

The reaction mixture was then cooled down to 5° C. To the reactionmixture was added concentrated HCl (1090 mL, 13.28 mol) whilemaintaining the temperature at about 15-30° C. to adjust the pH to about4.3. The excess solid hydroquinone was removed by extraction with methylisobutyl ketone three times (1200 mL, 200 mL×2). The resulting aqueouslayer was further acidified to pH 1 with concentrated HCl (140 mL, 1.7mol). Most of the (S)-2-(4-hydroxylphenoxy)propionic acid became solidat this point. (S)-2-(4-hydroxylphenoxy)propionic acid was thenextracted into isopropyl acetate (800 mL and 400 mL). Water (325 mL) wasadded to the isopropyl acetate solution and the isopropyl acetate wasremoved azeotropically. The aqueous solution was adjusted to pH about2.2 with 50% NaOH, then cooled down slowly to 20° C. The crude solid wascollected by vacuum filtration and the filter cake was washed with smallamount of water. The crude solid was recrystallized from water (230 mL)to yield the title compound as a white granular solid of 100% ee.

mp 139-140° C.

Optical rotation: [α]²⁰ _(D)=−38.5 (c 1.0, MeOH)

MS: m/z(ESI−): 181.12 (M-H)⁻, m/z (ESI+): 204.96 (M+Na)⁺

¹H NMR (300 MHz, DMSO-d⁶) δ 12.85 (brs, 1H), 8.95 (brs, 1H), 6.68 (m,4H), 4.62 (q, J=6.8 Hz, 1H), 1.44 (d, J=6.8 Hz, 3H).

¹³C NMR (300 MHz, DMSO-d⁶) δ 173.8, 151.9, 150.6, 116.4, 116.0, 72.7,18.7,

FTIR (KBr): 3211 (br.), 1716, 1516, 1454, 1416, 1377, 1330, 1263, 1233,1176, 1136, 1098, 1045, 946, 918, 861, 826, 766, 712, 697, 673, 638,563, 508 cm⁻¹.

Elemental Analysis for C₉H₁₀O₄:

Calculated: C: 59.34H: 5.93

Found: C: 59.24H: 5.83

EXAMPLE 7 (R)-(−)-tert-Butyl2-(2-ethylamino-indan-5-visulfanyl)-2-methyl-Propionate,(S)-(−)-2-(4-hydroxyphenoxy)propionic acid salt

A solution of (S)-(−)-2-(4-hydroxyphenoxy)propionic acid (46.7 g) in 95%EtOH (200 mL) was warmed to about 30-35° C. To the solution was added asolution of the crude dark purple oil prepared in Example 5 above (94.5g, 0.25 mol, 89% pure) in 95% EtOH (227 mL). After addition, the mixturewas stirred and cooled down to 0° C. at the rate of less than 5° C. perhour. The suspension was then stirred at 0° C. for 2 hours, the solidwas collected by vacuum filtration.

The crude solid with 86% ee was dissolved in 95% ethanol (165 mL) at 60°C. The solution was cooled slowly to 20° C. and stirred at thistemperature for 18 hours. The solid was collected by vacuum filtrationto yield the product as a white granular solid with 99.5% ee.

mp 145.6-147.0° C.

Optical rotation: [α]²⁰ _(D)=−22.8 (c 1.0, MeOH).

¹H NMR (300 MHz, DMSO-d⁶) δ 7.26 (m, 3H), 6.62 (m, 4H), 4.35 (q, J=6.8Hz, 1H), 3.14 (m, 2H), 3.74 (p, J=7.2 Hz, 1H), 2.87 (dd, J=6.7 Hz, 16.3Hz, 2H), 2.76 (q, J=7.3 Hz, 2H), 1.36 (s, 9H), 1.35 (s, 6H), 1.34 (d,J=6.8 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H).

¹³C NMR (300 MHz, DMSO-d⁶) δ 175.8, 172.4, 151.5, 151.2, 142.3, 141.3,135.5, 132.9, 129.4, 125.0, 115.9, 115.7, 80.7, 74.8, 57.4, 51.2, 41.0,36.4, 27.8, 26.1, 19.3, 12.3.

FTIR (KBr): 2980, 2934, 1717, 1629, 1576, 1510, 1458, 1405, 1368, 1279,1257, 1230, 1148, 1121, 1101, 1044, 848, 830, 801, 758, 679, 643, 525cm⁻¹.

Elemental Analysis for C₂₈H₃₉NO₆S.0.43 EtOH:

Calculated: C: 64.19, H: 7.66, N: 2.13, S: 5.49

Found: C: 64.12, H: 7.87, N: 2.18, S: 5.89

EXAMPLE 8 (R)-(−)-tert-Butyl2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate

The diastereomeric salt prepared in Example 7 above (357 g, 0.635 mol)was charged into a mixture of isopropyl acetate (2 L) and 50% of NaOH(102 g, 1.28 mol) in water (0.8 L). The mixture was stirred until allsolids dissolved. After removal of the bottom aqueous layer, theisopropyl acetate layer was washed with water 3 times until the pH ofthe aqueous phase was about 7. The organic solution was concentrated at60° C. to remove about ¾ of the isopropyl acetate. 1 L of freshisopropyl acetate was added and the amount of residual water in thesolution was assayed by KF. The solution was used for the next stepdirectly.

An analytical sample was obtained as clear oil by simple concentrationof a small amount of the crude solution.

Optical Rotation: [α]²⁰ _(D)=−17.1 (c 1.0, MeOH).

MS (APCl): m/z 336.3 (MH⁺).

¹H NMR (300 MHz, DMSO-d⁶) δ 7.26 (s, 1H), 7.19 (m, 2H), 3.50 (p, J=6.8Hz, 1H), 3.04 (dt, J=16 Hz, 6.5 Hz, 2H), 2.64 (m, 2H), 2.57 (q, J=7.0Hz, 2H), 1.36 (s, 9H), 1.34 (s, 6H), 1.01 (t, J=7.0 Hz, 3H).

¹³C NMR (300 MHz, DMSO-d⁶) δ 172.0, 143.8, 142.8, 134.5, 132.6, 128.2,124.6, 80.2, 59.2, 50.7, 41.7, 39.3, 27.4, 25.7, 15.2.

FTIR (ReactIR, neat): 2971, 2933, 2838, 1721, 1474, 1461, 1385, 1366,1343, 1275, 1256, 1146, 1121, 1036, 1009, 942, 847, 820, 752, 706 cm⁻¹.

Elemental Analysis for C₁₉H₂₉NO₂S:

Calculated: C, 68.02; H, 8.71; N, 4.17; S, 9.56

Found: C, 67.94,H, 8.93, N, 4.09, S, 9.54.

EXAMPLE 9 (R)-(+)-tert-Butyl2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionate

To a solution of tert-butyl2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate (182 g, 0.544mol) was added 4-(trifluoromethoxy)phenyl isocyanate (115 g, 0.556 mol)and the reaction temperature was maintained at about 15-20° C. Afteraddition, the clear solution was stirred for 15 minutes at about 15-20°C. The solution was used for the next step directly.

An analytical sample was obtained as a white solid by simpleconcentration of a small amount of the crude solution.

mp 95.4-97.8° C.

Optical rotation: [a]²⁰ _(D)=+3.4 (c 1.0, MeOH).

MS (APCI): m/z 280.2(30% ), 306.2(100% ), 437.3(50% ), 483.1(20%).

¹H NMR (300 MHz, DMSO-d⁶) δ 8.48 (s, 1H), 7.61 (d, J=9.2 Hz, 2H), 7.27(m, 5H), 4.91 (p, J=8.2 Hz, 1H), 3.37 (q, J=6.8 Hz, 2H), 3.08 (m, 4H),1.38 (s, 9H), 1.36 (s, 6H), 1.09 (t, J=6.8 Hz, 3H).

¹³C NMR (300 MHz, DMSO-d⁶) δ 15.5, 26.1, 27.8, 36.6, 38.4, 51.2, 56.8,80.7, 120.6 (q, J=225 Hz, OCF₃), 121.4, 121.5, 124.9, 129.1, 132.8,135.3, 140.2, 142.3, 143.0, 143.3, 154.9, 172.5,

FTIR (KBr): 3297, 2974, 2933, 1724, 1636, 1605, 1511, 1419, 1369, 1270,1229, 1198, 1148, 1122, 845, 817, 756, 561 cm⁻¹.

Elemntal Analysis for C₂₇H₃₃F₃N₂O₄S:

Calculated: C, 60.21; H, 6.18; N, 5.20; F, 10.58; S, 5.95

Found: C, 59.87; H, 6.22; N, 5.08; F, 10.86; S, 5.94.

EXAMPLE 10(R)-(+)-2-{2-[1-Ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionicacid

To a solution of tert-butyl2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionate(288 g, 0.534 mol) was added a solution of sulfuric acid (535 g, 5.34mol) in isopropyl acetate (0.7 L) while maintaining the reactiontemperature at about 15-20° C. The clear solution was stirred at 15° C.for 1 hour after the addition. To the reaction mixture was added coldwater (0.94 L). After removal of the acidic aqueous layer, the isopropylacetate layer was washed until the pH of the aqueous layer reached 3.The solution was used in the next step without isolation.

An analytical sample was obtained as a white foam by simpleconcentration of a small amount of the crude solution.

mp 57° C.

Optical rotation: [α]²⁰ _(D)=+7.7 (c 1.0, MeOH).

MS (APCI): m/z: 483.1(MH⁺).

¹H NMR (300 MHz, DMSO-d⁶) δ 12.43 (br s, 1H), 8.49 (s, 1H), 7.61 (d,J=9.5, 2H), 7.27 (m, 5H), 4.91 (p, J=8.4 Hz, 1H), 3.39 (m, 2H), 3.08 (m,4H), 1.38 (s, 6H), 1.10 (t, J=6.9 Hz, 3H).

¹³C NMR (300 MHz, DMSO-d⁶) δ 175.2, 154.9, 143.2, 143.0, 142.3, 140.2,135.1, 132.6, 129.4, 125.0, 121.5, 121.3, 120.6 (q, J=255 Hz, OCF₃),56.8, 51.0, 38.4, 36.5, 26.0, 15.5.

FTIR (KBr): 3395, 2977, 2935, 1703, 1641, 1511, 1420, 1265, 1200, 1161,1016, 841, 815, 755 cm⁻¹.

Elemental Analysis for C₂₃H₂₅F₃N₂O₄S:

Calculated: C, 57.25; H, 5.22; N, 5.81; F, 11.81; S, 6.65.

Found: C, 57.00; H, 5.47; N, 5.41; F, 11.75; S, 6.23.

EXAMPLE 11(R)-(+)-2-{2-[1-Ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionicacid, N,N′-dibenzylethylenediamine salt

Seeds Preparation:

N,N′-Dibenzylethylenediamine (0.26 g, 1.08 mmol) was added to t-butylmethyl ether solution of2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionicacid (0.52 g, 1.08 mmol). iPrOAc was added to the resulted cloudysolution. The solution was kept in the refrigerator overnight (˜20hours). The solids precipitated were collected by filtration. ¹H NMRanalysis and the melting point measurement of the isolated solidsconfirmed the formation of the salt with 1:1 mole ratio of acid andN,N′-dibenzylethylenediamine.

Salt Preparation:

A solution of2-{2-[1-ethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-indan-5-ylsulfanyl}-2-methyl-propionicacid (218.51 g, 0.453 mol) in isopropyl acetate (859 mL) was cooled toabout −5 to 0° C. and N,N′-dibenzylethylenediamine (112 g, 0.453 mol)was added over 1 hour. The internal reaction temperature was maintainedunder 0° C. Heptane (513 mL) was added to the solution until thesolution became cloudy. The seeds were added while stirring. The cloudymixture changed to a uniform suspension within one hour. Additionalheptane (60 mL) was then added. After stirred for 1 h, more heptane (180mL) was added. The suspension was stirred overnight (18 hours) at 0° C.

The solid was filtered and rinsed with a chilled mixture ofiPrOAc/heptane (½, 90 mL). The solid was air-dried at the ambienttemperature overnight to yield a solid with 99.1% ee.

mp 99-102° C.

Optical rotation: [a]²⁰ _(D)═+7.7 (c 1.0, MeOH).

MS (APCI): m/z 483.8(MH⁺).

¹H NMR (300 MHz, DMSO-d⁶) δ 8.54 (s, 1H), 7.63 (m, 2H), 7.28 (m, 15H),6.99 (br s, 3H), 4.91 (p, J=8.5 Hz, 1H), 3.80 (s, 4H), 3.37 (q, J=6.9Hz, 2H), 3.05 (d, J=7.6 Hz, 4H), 2.77 (s, 4H), 1.33 (s, 6H), 1.09 (t,J=6.9 Hz, 3H).

¹³C NMR (300 MHz, DMSO-d⁶) δ 176.6, 154.9, 142.9, 142.1, 141.9, 140.3,138.8, 134.7, 132.2, 131.3, 128.8, 128.5,127.4, 124.7, 121.4, 121.4,120.2 (q, J=255 Hz, OCF₃), 56.8, 52.9, 52.2, 46.7, 38.3, 36.5, 36.4,27.3, 15.5.

FTIR (KBr): 3310(broad), 2972, 2849, 1638, 1606, 1539, 1510, 1458, 1418,1389, 1351, 1264, 1244, 1199, 1162, 842, 816, 748, 698.81, 668 cm⁻¹.

Elemental Analysis for C₃₉H₄₅F₃N₄O₄S:

Calculated: C 64.80; H 6.27; N, 7.75; F 7.88; S, 4.44

Found: C, 64.65; H, 6.35; N, 7.61; F, 8.12, S, 4.51.

EXAMPLE 12 (S)-(+)-tert-Butyl2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate,(S)-(−)-2-(4-hydroxyphenoxy)propionic acid salt

Racemic tert-Butyl2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate (0.30 mmol) and(S)-(−)-2-(4-hydroxyphenoxy)propionic acid (0.30 mmol) were mixed intoTHF (2 mL) and heated to 50° C. to a clear solution. The reactionmixture was then cooled to the ambient temperature and stirredovernight. White crystalline solid precipitated and determined to be theenriched diastereomeric salt (S)-(+)-tert-Butyl2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate and(S)-(−)-2-(4-hydroxyphenoxy)propionic acid at 48% ee by chiral HPLC.

EXAMPLE 13 (S)-(+)-tert-Butyl2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-prolionate.(S)-(−)-2-(4-hydroxyphenoxy)propionic acid salt

Racemic tert-Butyl2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate (17 g, 51 mmol)and (S)-(−)-2-(4-hydroxyphenoxy)propionic acid (4.6 g, 25 mmol) weredissolved in acetone (55 mL), each separately. The solutions were thenmixed and stirred at the ambient temperature overnight. The resultingthick suspension was heated to 55° C. for 6 h, 40° C. for 18 h, thenheated to 50° C. and filtered to yield a solid which was determined tobe enriched with the diastereomeric salt (S)-(+)-tert-Butyl2-(2-ethylamino-indan-5-ylsulfanyl)-2-methyl-propionate and(S)-(−)-2-(4-hydroxyphenoxy)propionic at 22% ee. The enriched salt wasre-crystallized from acetone twice, to yield the title compound salt(S,S) salt in 94% ee.

¹H NMR for 94% ee sample (300 MHz, DMSO-d⁶) δ 7.26 (m, 3H), 6.62 (m,4H), 4.35 (q, J=6.8 Hz, 1H), 3.14 (m, 2H), 3.74 (p, J=7.2 Hz, 1H), 2.87(dd, J=6.7 Hz, 16.3 Hz, 2H), 2.76 (q, J=7.3 Hz, 2H), 1.36 (s, 9H), 1.35(s, 6H), 1.34 (d, J=6.8 Hz, 3H), 1.10 (t, J=7.3 Hz, 3H).

m.p. for 80% ee sample isolated after first recrystallization asdescribed above: 157-159° C. (DSC)

EXAMPLE 142-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthale-2-ylsulfanyl}-2-methylpropionicacid

STEP A. 7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine

To a solution of 7-methoxy-2-tetralone (12.4 g; 70.7 mmol) dissolved inMeOH (350 mL) was added ammonium acetate (82 g; 1.06 mol) and thereaction was stirred for 30 min at room temperature. To the reaction wasthen added sodium cyanoborohydride (21.5 g; 353 mmol) and the reactionwas refluxed for 1 h. Upon completion of the reaction, the reaction wascooled and the solvent removed under reduced pressure. The residue wasdiluted with EtOAc and 1 N NaOH was added to quench the reaction. Theaqueous phase was separated and the organic phase washed with H₂O,brine, dried over Na₂SO₄, filtered, and the solvent removed underreduced pressure to yield7-methoxy-1,2,3,4-tetrahydronapthalen-2-ylamine as a dark oil.

MS, m/z: 178 (M+1) C₁₁H₁₅NO.

STEP B. N-(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide

To a stirred suspension of7-methoxy-1,2,3,4-tetrahydronapthalen-2-ylamine (2.54 g; 14.3 mmol) inCH₂Cl₂ (20 mL) was added DIEA (3.4 mL) and the reaction mixture wascooled to 0° C. Acetyl chloride (1.22 mL; 17.1 mmol) was added dropwiseat 0° C. and the reaction was allowed to warm to room temperature, thenstirred for 18 h. The reaction mixture was diluted with CH₂Cl₂, washedwith H₂O, dried over Na₂SO₄, filtered and the solvent removed underreduced pressure to yield a crude solid. Purification by flashchromatography (SiO₂) eluting with hexanes-EtOAc yieldedN-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide as a whitesolid.

MS, m/z: 220 (M+1) C₁₃H₁₇NO₂.

STEP C. 6-Acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonylchloride

To chlorosulfonic acid (15 mL), cooled to −10° C. was addedN-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (1.44 g; 6.6mmol). The reaction mixture was stirred at −10° C. for 15 min andquenched carefully by pouring over ice-water. The aqueous phase wasextracted with CH₂Cl₂ (3X), the organic extracts combined, dried overNa₂SO₄, filtered and evaporated under reduced pressure to yield6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonylchloride as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 7.68 (s, 1H), 6.78 (s, 1H), 5.53-5.56 (m,1H), 4.22-4.31 (m, 1H), 4.00 (s, 3H), 3.18-3.26 (dd, 1H), 2.86-2.90 (m,2H), 2.67-2.76 (dd, 1H), 2.04-2.12 (m, 1H), 2.00 (s, 1H), 1.73-1.82 (m,2H).

MS, m/z: 318 (M+1) C₁₃H₁₆ClNO₄S.

STEP D.N-(6-Mercaito-7-methoxy-1,2,3,4-tetrahydronaphthalen-2yl)acetamide

To a suspension of zinc dust (1.16 g; 17.7 mmol) and dimethylsilyldichloride (2.4 mL; 17.7 mmol) in MeCN (40 mL) was added a solution of6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonylchloride (1.13 g; 3.55 mmol) in MeCN/DCE (40/10 mL), at roomtemperature. The reaction suspension was then heated at 81° C. for 4 h,cooled to room temperature, filtered and the solvent evaporated underreduced pressure. The crude residue was purified by reverse-phasesemi-prep HPLC eluting with a MeCN—H₂O gradient to yieldN-(6-mercapto-7-methoxy-1,2,3,4-tetrahydronaphthalen-2 yl)acetamide as awhite solid andN-[6-(6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2yldisulfanyl)-7-methoxy-1,2,3,4,-tetrahydronaphthalen-2-yl]acetamideas a tan solid.

MS, m/z: 252 (M+1; S—H) C₁₃H₁₇NO₂S & 501 (M+1; S—S) C₂₆H₃₂N₂O₄S₂.

STEP E.2-(6-Acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionicacid tert-butyl ester

To a suspension ofN-[6-(6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2yl]disulfanyl)-7-methoxy-1,2,3,4,-tetrahydronaphthalen-2-yl]acetamide(0.368 g; 0.73 mmol) in MeOH (10 mL) was added DMF (3 mL), K₂CO₃ (0.31g; 2.26 mmol), tert-butyl 2-bromoisobutyrate (0.66 mL; 2.95 mmol) andNaBH₄ (0.28 g; 7.34 mmol) and the reaction mixture was stirred for 18 hat room temperature. The reaction mixture was partitioned between EtOAcand H₂O, the aqueous phase extracted with EtOAc, the organic extractscombined, washed with H₂O, brine, dried over Na₂SO₄, filtered and thesolvent removed under reduced pressure to yield a crude oil, which waspurified by reverse-phase semi-prep HPLC eluting with a MeCN—H₂O.gradient to yield2-(6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionicacid tert-butyl ester as an oil.

MS, m/z: 338 (M+1) C₂₁H₃₁NO₄S.

STEP F.2-(6-Ethylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionicacid tert-butyl ester

To a solution of2-(6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionicacid tert-butyl ester (0.68 g; 1.74 mmol) in THF (15 mL) was added asolution of 1.0 M borane-THF (15 mL), dropwise at room temperature. Thereaction mixture was allowed to stir for 18 h at room temeperature, thencarefully quenched with MeOH (10 mL) and the solvent evaporated underreduced pressure. The residual oil was further azeotroped with MeOH (3×)to yield a mixture of2-(6-ethylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionicacid tert-butyl ester and it's borane complex as an oil.

MS, m/z: 380 (M+1) C₂₁H₃₃NO₃S.

STEP G.2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl-2-methylpropionicacid tert butyl ester

To a mixture of2-(6-ethylamino-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methylpropionicacid tert-butyl ester and borane complex (0.054 g; 0.141 mmol) dissolvedin CH₂Cl₂ (2 mL) was added 4-trifluoromethoxyphenyl isocyanate (0.063mL; 0.284 mmol) and the reaction mixture as stirred at room temperaturefor 18 h. The solvent was removed under reduced pressure and the cruderesidue was purified by reverse-phase semi-prep HPLC eluting with aMeCN—H₂O. gradient to yield2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionicacid tert butyl ester as an oil.

MS, M/Z: 527 ((M-C₄H₈)+1) C₂₉H₃₇F₃N₂O₅S.

STEP H.2-{6-[1-Ethyl-3-(4-trifluoromethoxyohenyl)ureidol-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl]-2-methylpropionicacid

To2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionicacid tert butyl ester (0.02 g; 0.03 mmol) dissolved in CH₂Cl₂ (1.5 mL)was added TFA (1.5 mL) and the reaction mixture was stirred at roomtemperature for 1.5 h. The solvent was removed under reduced pressureand the residue was purified by reverse-phase semi-prep HPLC elutingwith a MeCN—H₂O. gradient to yield2-{6-[1ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionicacid as a white solid.

¹H NMR (300 MHz, CD₃OD): δ 7.45-7.48 (d, 2H), 7.15-7.18 (m, 3H), 6.71(s, 1H), 4.43-4.79 (m, 1H), 3.75 (s, 3H), 3.43-3.45 (m, 2H), 2.88-3.08(m, 4H), 1.99-2.03 (m, 2H), 1.38 (s, 6H), 1.25-1.52 (t, 3H).

MS, m/z: 526 (M+1) C₂₅H₂₉F₃N₂O₅S.

The following compounds were similarly prepared according to the 15procedure described in Example 14 above with selection and substitutionof suitable reagents and reaction conditions.

EXAMPLE 152-{6-[3-(4-tert-Butylphenyl)1-ethylureidol-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylprooionicacid

Prepared as an oil by replacing 4-trifluoromethoxyphenyl isocyanate with4-tert-butylphenyl isocyanate in Step G above.

MS, m/z: 499 (M+1) C₂₈H₃₈N₂O₄S.

EXAMPLE 162-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl]-2-methylpropionicacid

Prepared as a white solid by substituting 7-methoxy-2-tetralone with7-fluoro-2-tetralone in STEP A above.

¹H NMR (300 MHZ, CDCL₃): δ 7.46-7.51 (M, 2H), 7.25-7.28 (D, 1H),7.17-7.20 (D, 2H), 6.92-6.95 (D, 1H), 4.43 (M, 1H), 3.42-3.49 (M, 2H),2.90-3.11 (M, 4H), 2.02-2.07 (M, 2H), 1.45 (S, 6H), 1.25-1.31 (T, 3H).

MS, m/z: 515 (M+1) C₂₄H₂₆F₄N₂O₄S.

EXAMPLE 172-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-chloro-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl-2-methylpropionicacid

Prepared as a white solid by substituting 7-methoxy-2-tetralone with7-chloro-2-tetralone in STEP A above.

MS, m/z: 532 (M+1) C₂₄H₂₆ClF₃N₂O₄S.

EXAMPLE 182-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-bromo-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methyylropionicacid

Prepared as a white solid by substituting 7-methoxy-2-tetralone with7-bromo-2-tetralone in STEP A above.

¹H NMR (300 MHz, CDCl₃): δ 7.45-7.48 (m, 3H), 7.36 (s, 1H), 7.15-7.18(d, 2H), 4.41-4.79 (m, 1H), 3.40-3.47 (m, 2H), 2.90-3.07 (m, 4H),2.01-2.03 (m, 2H), 1.45 (s, 6H), 1.24-1.29 (t, 3H).

MS, m/z: 576 (M+1) C₂₄H₂₆BrF₃N₂O₄S.

EXAMPLE 192-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-methyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl-2-methylpropionicacid

Prepared as a white solid by substituting 7-methoxy-2-tetralone with7-methyl-2-tetralone in STEP A above.

¹H NMR (300 MHz, CDCl₃): δ 7.45-7.48 (m, 2H), 7.22 (s, 1H), 7.15-7.18(d, 2H), 7.02 (s,1H), 4.41-4.79 (m, 1H), 3.40-3.47 (m, 2H), 2.85-3.03(m, 4H), 2.39 (s, 3H), 2.01-2.03 (m, 2H), 1.41 (s, 6H), 1.24-1.29 (t,3H).

MS, m/z: 511 (M+1) C₂₅H₂₉F₃N₂O₄S.

EXAMPLE 202-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-trifluoromethoxy-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl]-2-methylpropionicacid

Prepared as white solid by substituting 7-methoxy-2-tetralone with7-methyl-2-tetralone in STEP A above.

¹H NMR (300 MHz, CDCl₃): δ 7.45-7.48 (d, 2H), 7.37 (s, 1H), 7.12-7.18(m, 3H), 4.44 (m, 1H), 3.43-3.48 (m, 2H), 2.97-3.21 (m, 4H), 2.03-2.05(m, 2H), 1.42 (s, 6H), 1.25-1.30 (t, 3H).

MS, m/z: 580 (M+1) C₂₅H₂₆F₆N₂O₅S.

EXAMPLE 212-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureidol-3-phenyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionicacid

STEP A.2-(6-Acetylamino-3-Phenyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylprolionicacid tert-butyl ester

To2-(6-acetylamino-3-bromo-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionicacid tert-butyl ester (0.135 g; 0.30 mmol) dissolved in toluene (1.5 mL)was added phenylboronic acid (0.178 g; 1.46 mmol), Pd(PPh₃)₄ (15 mg;0.013 mmol) and 2M Na₂CO₃ (0.61 mL) and the reaction mixture heated at95° C. for 18 h. The reaction mixture was cooled, diluted with EtOAc,washed with H₂O. (2×), brine, dried over Na₂SO₄, filtered and thesolvent removed under reduced pressure to yield a crude residue whichwas purified by flash chromatography (SiO₂) eluting with a heptane-EtOAcgradient (50→100% ) to yield2-(6-acetylamino-3-phenyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methyl-propionicacid tert-butyl ester as a clear oil.

MS, M/Z: 383 ((M-C₄H₈)+1) C₂₆H₃₃NO₃S

2-{6-[1-Ethyl-3-(4-trifluoromethoxyphenyl)ureido]-3-phenyl-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionicacid, the compound of Example 21 was additionally prepared, as a whitesolid, according to the procedure described in Example 14, by selectingand substituting suitable reagents in Steps F, G and H, as appropriate.

¹H NMR (300 MHz, CDCl₃): δ 7.45-7.48 (d, 2H), 7.29-7.38 (m, 6H),7.15-7.18 (d, 2H), 7.10 (s, 1H), 4.46 (m, 1H), 3.44-3.49 (m, 2H),2.98-3.06 (m, 4H), 2.04-2.06 (m, 2H), 1.26-1.30 (t, 3H), 1.14 (s, 6H).

MS, M/Z: 573 (M+1) C₂₅H₂₉F₃N₂O₅S

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations.and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A process for the preparation of a compound of formula (L)

wherein Q is selected from the group consisting of OH, OPg², NH₂ andN(Pg³Pg⁴); wherein Pg² is a carboxylic acid protecting group; andwherein Pg³ and Pg⁴ are each independently selected from hydrogen,C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are taken togetherwith the nitrogen atom to which they are bound to form C₃₋₁₀heteroarylor C₃₋₁₀non-aromatic heterocyclic; each of R₁ and R₂ is independently H,C₁₋₆alkyl, (CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or(CH₂)_(m)CO₂R₈; wherein each of R_(a), R_(b), and R₈ is independently Hor C₁₋₆alkyl; and m is an integer from 1 to 6; alternatively, R₁ and R₂are taken together with the carbon atom to which they are attached toform a C₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; providedthat when n is 1, X is bound at the 5 or 6 position; and when n is 2, Xis bound at the 6 or 7 position; provided further that when n is 2 and Xis bound at the 6 position, then R³ is other than hydrogen and bound atthe 7 position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl,NR₉R₁₀, NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X;provided that R₃ is other than CF₃; each R₉ and R₁₀ is independentlyC₁₋₆alkyl; R₄ is H or —(C₁₋₅straight chain alkylene)R₁₅; wherein R₁₅ isH, C₁₋₇alkyl, [di(C₁₋₂alkyl)amino](C₁₋₆alkylene)—,(C₁₋₃alkoxyacyl)(C₁₋₆alkylene)—, C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl;wherein R₄ has no more than 9 carbon atoms; alternatively, R₄ is—(straight chain C₁₋₅alkylene)R₁₆; wherein R₁₆ is C₃₋₆cycloalkyl or a5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatomsselected from N, O, and S; wherein each of the above hydrocarbyl andheterocarbyl moieties may be optionally substituted with between 1 and 3substituents independently selected from F, Cl, Br, I, amino, methyl,ethyl, hydroxy or methoxy; comprising

reacting a compound of formula (III), to yield the correspondingcompound of formula (IV), wherein Pg₁ is a nitrogen protecting groupwhich is inert to ClSO₃H;

reacting the compound of formula (IV) with a suitably substitutedcompound of formula (V) wherein R_(4a) is R₄ other than hydrogen andwherein J is Br, Cl or I, in the presence of a base, to yield thecorresponding compound of formula (VI); and then reacting the compoundof formula (VI) with ClSO₃H, to yield the corresponding compound offormula (VII); alternatively, reacting the compound of formula (IV) withClSO₃H, to yield the corresponding compound of formula (VII) wherein R₄is hydrogen;

reacting the compound of formula (VII) with a reducing agent capable ofreducing the chlorosulfonyl group on the compound of formula (VII), toyield a mixture of the corresponding compound of formula (VIII) and thecorresponding compound of formula (IX);

reacting the compound of formula (VIII), isolated or in a mixture withthe compound of formula (IX), with a suitably substituted compound offormula (X), wherein W is Br, Cl or I, in the presence of a base, toyield the corresponding compound of formula (XI); alternatively,reacting the compound of formula (IX), isolated or in a mixture with thecompound of formula (VIII), with a reducing agent capable of reducingthe disulfide on compound of formula (IX), to yield the correspondingcompound of formula (VIII); and then reacting the compound of formula(VIII) with a suitably substituted compound of formula (X), wherein W isBr, Cl or I, in the presence of a base, to yield the correspondingcompound of formula (XI);

reacting the compound of formula (XI), to yield the correspondingcompound of formula (L).
 2. A process for the preparation of a compoundof formula (I)

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆ amide thereof,wherein each of R₁ and R₂ is independently H, C₁₋₆alkyl,(CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or (CH₂)_(m)CO₂R₈;wherein each of R_(a), R_(b), and R₈ is independently H or C₁₋₆alkyl;and m is an integer from 1 to 6; alternatively, R₁ and R₂ are takentogether with the carbon atom to which they are attached to form aC₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; provided that whenn is 1, X is bound at the 5 or 6 position; and when n is 2, X is boundat the 6 or 7 position; provided further that when n is 2 and X is boundat the 6 position, then R³ is other than hydrogen and bound at the 7position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X; provided thatR₃ is other than CF₃; each R₉ and R₁₀ is independently C₁₋₆alkyl; R₄ isH or —(C₁₋₅straight chain alkylene)R₁₅; wherein R₁₅ is H, C₁₋₇alkyl,[di(C₁₋₂alkyl)amino](C₁₋₆alkylene)—, (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)—,C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl; wherein R₄ has no more than 9carbon atoms; alternatively, R₄ is —(straight chain C₁₋₅alkylene)R₁₆;wherein R₁₆ is C₃₋₆cycloalkyl or a 5-6 membered non-aromaticheterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;c is an integer from 0 to 1; each of R₅ and R₇ is independently selectedfrom H, C₁₋₆alkyl, halo, cyano, nitro, COR₁₁, COOR₁₁, C₁₋₁₄alkoxy,C₁₋₁₄alkylthio, hydroxy, phenyl, NR₁₁R₁₂ or a 5-6 membered heterocyclylwith between 1 and 2 heteroatoms selected from N, O, and S; R₆ isselected from C₁₋₆alkyl, halo, cyano, nitro, COR₁₃, COOR₁₃, C₁₋₄alkoxy,C₁₋₄alkylthio, hydroxy, phenyl, NR₁₃R₁₄ or a 5-6 membered heterocyclylwith between 1 and 2 heteroatoms selected from N, O, and S;alternatively, R₅ and R₆ or R₆ and R₇ may be taken together to be abivalent moiety, saturated or unsaturated, selected from C₃₋₄alkylene,C₃₋₄alkenylene or (CH₁₋₂)_(p)N(CH₁₋₂)_(q); p is an integer from 0 to 2and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;each R₁₁, R₁₂, R₁₃ and R₁₄ is independently H or C₁₋₆alkyl; wherein eachof the above hydrocarbyl and heterocarbyl moieties may be optionallysubstituted with between 1 and 3 substituents independently selectedfrom F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy; comprisingthe process of claim 1 and further comprising

reacting the compound of formula (L), to yield the correspondingcompound of formula (I).
 3. A process for the preparation of a compoundof formula (I)

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆ amide thereof,wherein each of R₁ and R₂ is independently H, C₁₋₆alkyl,(CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or (CH₂)_(m)CO₂R₈;wherein each of R_(a), R_(b), and R₈ is independently H or C₁₋₆alkyl;and m is an integer from 1 to 6; alternatively, R₁ and R₂ are takentogether with the carbon atom to which they are attached to form aC₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; provided that whenn is 1, X is bound at the 5 or 6 position; and when n is 2, X is boundat the 6 or 7 position; provided further that when n is 2 and X is boundat the 6 position, then R³ is other than hydrogen and bound at the 7position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X; provided thatR₃ is other than CF₃; each R₉ and R₁₀ is independently C₁₋₆alkyl; R₄ isH or —(C₁₋₅straight chain alkylene)R₁₅; wherein R₁₅ is H, C₁₋₇alkyl,[di(C₁₋₂alkyl)amino](C₁₋₆alkylene)—, (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)—,C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl; wherein R₄ has no more than 9carbon atoms; alternatively, R₄ is —(straight chain C₁₋₅alkylene)R₁₆;wherein R₁₆ is C₃₋₆cycloalkyl or a 5-6 membered non-aromaticheterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;c is an integer from 0 to 1; each of R₅ and R₇ is independently selectedfrom H, C₁₋₆alkyl, halo, cyano, nitro, COR₁₁, COOR₁₁, C₁₋₄alkoxy,C₁₋₄alkylthio, hydroxy, phenyl, NR₁₁R₁₂ or a 5-6 membered heterocyclylwith between 1 and 2 heteroatoms selected from N, O, and S; R₆ isselected from C₁₋₆alkyl, halo, cyano, nitro, COR₁₃, COOR₁₃, C₁₋₄alkoxy,C₁₋₄alkylthio, hydroxy, phenyl, NR₁₃R₁₄ or a 5-6 membered heterocyclylwith between 1 and 2 heteroatoms selected from N, O, and S;alternatively, R₅ and R₆ or R₆ and R₇ may be taken together to be abivalent moiety, saturated or unsaturated, selected from C₃₋₄alkylene,C₃₋₄alkenylene or (CH₁₋₂)_(p)N(CH₁₋₂)_(q); p is an integer from 0 to 2and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;each R₁₁, R₁₂, R₁₃ and R₁₄ is independently H or C₁₋₆alkyl; wherein eachof the above hydrocarbyl and heterocarbyl moieties may be optionallysubstituted with between 1 and 3 substituents independently selectedfrom F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy; comprising

reacting a compound of formula (III), to yield the correspondingcompound of formula (IV), wherein Pg¹ is a nitrogen protecting groupwhich is inert to ClSO₃H;

reacting the compound of formula (IV) with a suitably substitutedcompound of formula (V) wherein R_(4a) is R₄ other than hydrogen andwherein J is Br, Cl or I, in the presence of a base, to yield thecorresponding compound of formula (VI); and then reacting the compoundof formula (VI) with ClSO₃H, to yield the corresponding compound offormula (VII); alternatively, reacting the compound of formula (IV) withClSO₃H, to yield the corresponding compound of formula (VII) wherein R₄is hydrogen;

reacting the compound of formula (VII) with a reducing agent capable ofreducing the chlorosulfonyl group on the compound of formula (VII), toyield a mixture of the corresponding compound of formula (VIII) and thecorresponding compound of formula (IX);

reacting the compound of formula (VIII), isolated or in a mixture withthe compound of formula (IX), with a suitably substituted compound offormula (X), wherein Q is selected from the group consisting of OH,OPg², NH₂ and N(Pg³Pg⁴); wherein Pg² is a carboxylic acid protectinggroup; and wherein Pg³ and Pg⁴ are each independently selected fromhydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are takentogether with the nitrogen atom to which they are bound to formC₃₋₁₀heteroaryl or C₃₋₁₀non-aromatic heterocyclic; and wherein W is Br,Cl or I, in the presence of a base, to yield the corresponding compoundof formula (XI); alternatively, reacting the compound of formula (IX),isolated or in a mixture with the compound of formula (VIII), with areducing agent capable of reducing the disulfide on compound of formula(IX), to yield the corresponding compound of formula (VIII); and thenreacting the compound of formula (VIII) with a suitably substitutedcompound of formula (X), wherein Q is selected from the group consistingof OH, OPg², NH₂ and N(Pg³Pg⁴); wherein Pg² is a carboxylic acidprotecting group; and wherein Pg³ and Pg⁴ are each independentlyselected from hydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ andPg⁴ are taken together with the nitrogen atom to which they are bound toform C₃₋₁₀heteroaryl or C₃₋₁₀non-aromatic heterocyclic; and wherein W isBr, Cl or I, in the presence of a base, to yield the correspondingcompound of formula (XI);

reacting the compound of formula (XI), to yield the correspondingcompound of formula (L);

reacting the compound of formula (L), to yield the correspondingcompound of formula (I).
 4. The process of claim 1 wherein Q is OPg²,Pg² is t-butyl, X is S, R₁ is methyl, R₂ is methyl, the—X—C(R₁R₂)—C(O)-Q group is bound at the 5-position, R₃ is hydrogen, n is1 and R₄ is ethyl
 5. The process of claim 2 wherein X is S, R₁ ismethyl, R₂ is methyl, the —X—C(R₁R₂)—C(O)—OH group is bound at the5-position, R₃ is hydrogen, n is 1, R₄ is ethyl, c is 0, R₅ is hydrogen,R₆ is trifluoromethoxy and R₇ is hydrogen.
 6. The process of claim 3wherein X is S, R₁ is methyl, R₂ is methyl, the —X—C(R₁R₂)—C(O)—OH groupis bound at the 5-position, R₃ is hydrogen, n is 1, R₄ is ethyl, c is 0,R₅ is hydrogen, R₆ is trifluoromethoxy and R₇ is hydrogen.
 7. A processfor the preparation of a compound of formula (L)

wherein Q is selected from the group consisting of OH, OPg², NH₂ andN(Pg³Pg⁴); wherein Pg² is a carboxylic acid protecting group; andwherein Pg³ and Pg⁴ are each independently selected from hydrogen,C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are taken togetherwith the nitrogen atom to which they are bound to form C₃₋₁₀heteroarylor C₃₋₁₀non-aromatic heterocyclic; each of R₁ and R₂ is independently H,C₁₋₆alkyl, (CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or(CH₂)_(m)CO₂R₈; wherein each of R_(a), R_(b), and R₈ is independently Hor C₁₋₆alkyl; and m is an integer from 1 to 6; alternatively, R₁ and R₂are taken together with the carbon atom to which they are attached toform a C₃₋₇cycloalkyl; n is an integer from 1 to 2; x is S; providedthat when n is 1, X is bound at the 5 or 6 position; and when n is 2, Xis bound at the 6 or 7 position; provided further that when n is 2 and Xis bound at the 6 position, then R³ is other than hydrogen and bound atthe 7 position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl,NR₉R₁₀, NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X;provided that R₃ is other than CF₃; each R₉ and R₁₀ is independentlyC₁₋₆alkyl; R₄ is H or —(C₁₋₅straight chain alkylene)R₁₅; wherein R₁₅ isH, C₁₋₇alkyl, [di(C₁₋₂alkyl)amino](C₁₋₆alkylene)—,(C₁₋₃alkoxyacyl)(C₁₋₆alkylene)—, C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl;wherein R₄ has no more than 9 carbon atoms; alternatively, R₄ is-(straight chain C₁₋₅alkylene)R₁₆; wherein R₁₆ is C₃₋₆cycloalkyl or a5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatomsselected from N, O, and S; wherein each of the. above hydrocarbyl andheterocarbyl moieties may be optionally substituted with between 1 and 3substituents independently selected from F, Cl, Br, I, amino, methyl,ethyl, hydroxy or methoxy; comprising

reacting a compound of formula (III), to yield the correspondingcompound of formula (IV), wherein Pg¹ is a nitrogen protecting groupwhich is inert to ClSO₃H;

reacting the compound of formula (IV) with a suitably substitutedcompound of formula (V) wherein R_(4a) is R₄ other than hydrogen andwherein J is Br, Cl or I, in the presence of a base, to yield thecorresponding compound of formula (VI); and then reacting the compoundof formula (VI) with ClSO₃H, to yield the corresponding compound offormula (VII); alternatively, reacting the compound of formula (IV) withClSO₃H, to yield the corresponding compound of formula (VII) wherein R⁴is hydrogen;

reacting the compound of formula (VII) with a reducing agent capable ofreducing the chlorosulfonyl group on the compound of formula (VII), toyield a mixture of the corresponding compound of formula (VIII) and thecorresponding compound of formula (IX);

de-protecting the compound of formula (VIII), isolated or in a mixturewith the compound of formula (IX), to yield the corresponding compoundof formula (XIII); alternatively, de-protecting the compound of formula(IX), isolated or in a mixture with the compound of formula (VIII), toyield a corresponding compound of formula (XII); and then reducing thecompound of formula (XII) with a reducing agent capable of reducing thedisulfide on compound of formula (XII), to yield the correspondingcompound of formula (XIII); alternatively still, reacting the compoundof formula (IX), isolated or in a mixture with the compound of formula(VIII), with a reducing agent capable of reducing the disulfide oncompound of formula (IX), to yield the corresponding compound of formula(VIII); and then de-protecting the compound of formula (VIII), to yieldthe corresponding compound of formula (XIII);

reacting the compound of (XIII) with a suitably substituted compound offormula (X), wherein W is Br, Cl or I, in the presence of a base, toyield the corresponding compound of formula (L).
 8. A process for thepreparation of a compound of formula (I)

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆ amide thereof,wherein each of R₁ and R₂ is independently H, C₁₋₆alkyl,(CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or (CH₂)_(m)CO₂R₈;wherein each of R_(a), R_(b), and R₈ is independently H or C₁₋₆alkyl;and m is an integer from 1 to 6; alternatively, R₁ and R₂ are takentogether with the carbon atom to which they are attached to form aC₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; provided that whenn is 1, X is bound at the 5 or 6 position; and when n is 2, X is boundat the 6 or 7 position; provided further that when n is 2 and X is boundat the 6 position, then R³ is other than hydrogen and bound at the 7position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X; provided thatR₃ is other than CF₃; each R₉ and R₁₀ is independently C₁₋₆alkyl; R₄ isH or —(C₁₋₅straight chain alkylene)R₁₅; wherein R₁₅ is H, C₁₋₇alkyl,[di(C₁₋₂alkyl)amino](C₁₋₆alkylene)—, (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)-,C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl; wherein R₄ has no more than 9carbon atoms; alternatively, R₄ is -(straight chain C₁₋₅alkylene)R₁₆;wherein R₁₆ is C₃₋₆cycloalkyl or a 5-6 membered non-aromaticheterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;c is an integer from 0 to 1; each of R₅ and R₇ is independently selectedfrom H, C₁₋₆alkyl, halo, cyano, nitro, COR₁₁, COOR₁₁, C₁₋₄alkoxy,C₁₋₄alkylthio, hydroxy, phenyl, NR₁₁R₁₂ or a 5-6 membered heterocyclylwith between 1 and 2 heteroatoms selected from N, O, and S;. R₆ isselected from C₁₋₆alkyl, halo, cyano, nitro, COR₁₃, COOR₁₃, C₁₋₄alkoxy,C₁₋₄alkylthio, hydroxy, phenyl, NR₁₃R₁₄ or a 5-6 membered heterocyclylwith between 1 and 2 heteroatoms selected from N, O, and S;alternatively, R₅ and R₆ or R₆ and R₇ may be taken together to be abivalent moiety, saturated or unsaturated, selected from C₃₋₄alkylene,C₃₋₄alkenylene or (CH₁₋₂)_(p)N(CH₁₋₂)_(q); p is an integer from 0 to 2and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;each R₁₁, R₁₂, R₁₃ and R₁₄ is independently H or C₁₋₆alkyl; wherein eachof the above hydrocarbyl and heterocarbyl moieties may be optionallysubstituted with between 1 and 3 substituents independently selectedfrom F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy; comprisingthe process of claim 7 and further comprising

reacting the compound of formula (L), to yield the correspondingcompound of formula (I).
 9. A process for the preparation of a compoundof formula (I)

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆amide thereof,wherein each of R₁ and R₂ is independently H, C₁₋₆alkyl,(CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or (CH₂)_(m)CO₂R₈;wherein each of R_(a), R_(b), and R₈ is independently H or C₁₋₆alkyl;and m is an integer from 1 to 6; alternatively, R₁ and R₂ are takentogether with the carbon atom to which they are attached to form aC₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; provided that whenn is 1, X is bound at the 5 or 6 position; and when n is 2, X is boundat the 6 or 7 position; provided further that when n is 2 and X is boundat the 6 position, then R³ is other than hydrogen and bound at the 7position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X; provided thatR₃ is other than CF₃; each R₉ and R₁₀ is independently C₁₋₆alkyl; R₄ isH or —(C₁₋₅straight chain alkylene)R₁₅; wherein R₁₅ is H, C₁₋₇alkyl,[di(C₁₋₂alkyl)amino](C₁₋₆alkylene)—, (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)-,C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl; wherein R₄ has no more than 9carbon atoms; alternatively, R₄ is -(straight chain C₁₋₅alkylene)R₁₆;wherein R₁₆ is C₃₋₆cycloalkyl or a 5-6 membered non-aromaticheterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;c is an integer from 0 to 1; each of R₅ and R₇ is independently selectedfrom H, C₁₋₆alkyl, halo, cyano, nitro, COR₁₁, COOR₁₁, C₁₋₄alkoxy,C₁₋₄alkylthio, hydroxy, phenyl, NR₁₁R₁₂ or a 5-6 membered heterocyclylwith between 1 and 2 heteroatoms selected from N, O, and S; R₆ isselected from C₁₋₆alkyl, halo, cyano, nitro, COR₁₃, COOR₁₃, C₁₋₄alkoxy,C₁₋₄alkylthio, hydroxy, phenyl, NR₁₃R₁₄ or a 5-6 membered heterocyclylwith between 1 and 2 heteroatoms selected from N, O, and S;alternatively, R₅ and R₆ or R₆ and R₇ may be taken together to be abivalent moiety, saturated or unsaturated, selected from C₃₋₄alkylene,C₃₋₄alkenylene or (CH₁₋₂)_(p)N(CH₁₋₂)_(q); p is an integer from 0 to 2and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;each R₁₁, R₁₂, R₁₃ and R₁₄ is independently H or C₁₋₆alkyl; wherein eachof the above hydrocarbyl and heterocarbyl moieties may be optionallysubstituted with between 1 and 3 substituents independently selectedfrom F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy; comprising

reacting a compound of formula (III), to yield the correspondingcompound of formula (IV), wherein Pg¹ is a nitrogen protecting groupwhich is inert to ClSO₃H;

reacting the compound of formula (IV) with a suitably substitutedcompound of formula (V) wherein R_(4a) is R₄ other than hydrogen andwherein J is Br, Cl or I, in the presence of a base, to yield thecorresponding compound of formula (VI); and then reacting the compoundof formula (VI) with ClSO₃H, to yield the corresponding compound offormula (VII); alternatively, reacting the compound of formula (IV) withClSO₃H, to yield the corresponding compound of formula (VII) wherein R⁴is hydrogen;

reacting the compound of formula (VII) with a reducing agent capable ofreducing the chlorosulfonyl group on the compound of formula (VII), toyield a mixture of the corresponding compound of formula (VIII) and thecorresponding compound of formula (IX);

de-protecting the compound of formula (VIII), isolated or in a mixturewith the compound of formula (IX), to yield the corresponding compoundof formula (XIII); alternatively, de-protecting the compound of formula(IX), isolated or in a mixture with the compound of formula (VIII), toyield a corresponding compound of formula (XII); and then reducing thecompound of formula (XII) with a reducing agent capable of reducing thedisulfide on compound of formula (XII), to yield the correspondingcompound of formula (XIII); alternatively still, reacting the compoundof formula (IX), isolated or in a mixture with the compound of formula(VIII), with a reducing agent capable of reducing the disulfide oncompound of formula (IX), to yield the corresponding compound of formula(VIII); and then de-protecting the compound of formula (VIII), to yieldthe corresponding compound of formula (XIII);

reacting the compound of (XIII) with a suitably substituted compound offormula (X), wherein Q is selected from the group consisting of OH,OPg², NH₂ and N(Pg³Pg⁴); wherein Pg²is a carboxylic acid protectinggroup; and wherein Pg³ and Pg⁴ are each independently selected fromhydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are takentogether with the nitrogen atom to which they are bound to formC₃₋₁₀heteroaryl or C₃₋₁₀non-aromatic heterocyclic; and wherein W is Br,Cl or I; in the presence of a base, to yield the corresponding compoundof formula (L);

reacting the compound of formula (L), to yield the correspondingcompound of formula (I).
 10. The process of claim 7 wherein Q is OPg²,Pg² is t-butyl, X is S, R₁ is methyl, R₂ is methyl, the—X—C(R₁R₂)—C(O)-Q group is bound at the 5-position, R₃ is hydrogen, n is1 and R₄ is ethyl
 11. The process of claim 8 wherein X is S, R₁ ismethyl, R₂ is methyl, the —X—C(R₁R₂)—C(O)—OH group is bound at the5-position, R₃ is hydrogen, n is 1, R₄ is ethyl, c is 0, R₅ is hydrogen,R₆ is trifluoromethoxy and R₇ is hydrogen.
 12. The process of claim 9wherein X is S, R₁ is methyl, R₂ is methyl, the-X—C(R₁R₂)—C(O)—OH groupis bound at the 5-position, R₃ is hydrogen, n is 1, R₄ is ethyl, c is 0,R₅ is hydrogen, R₆ is trifluoromethoxy and R₇ is hydrogen.
 13. A processfor the preparation of a compound of formula (L)

wherein Q is selected from the group consisting of OH, OPg², NH₂ andN(Pg³Pg⁴); wherein Pg² is a carboxylic acid protecting group; andwherein Pg³ and Pg⁴ are each independently selected from hydrogen,C₁₋₈alkyl, C₃₋₈cycloalkyl or and aryl; or Pg³ and Pg⁴ are taken togetherwith the nitrogen atom to which they are bound to form C₃₋₁₀heteroarylor C₃₋₁₀non-aromatic heterocyclic; each of R₁ and R₂ is independently H,C₁₋₆alkyl, (CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or(CH₂)_(m)CO₂R₈; wherein each of R_(a), R_(b), and R₈ is independently Hor C₁₋₆alkyl; and m is an integer from 1 to 6; alternatively, R₁ and R₂are taken together with the carbon atom to which they are attached toform a C₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; providedthat when n is 1, X is bound at the 5 or 6 position; and when n is 2, Xis bound at the 6 or 7 position; provided further that when n is 2 and Xis bound at the 6 position, then R³ is other than hydrogen and bound atthe 7 position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl,NR₉R₁₀, NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X;provided that R₃ is other than CF₃; each R₉ and R₁₀ is independentlyC₁₋₆alkyl; R₄ is —(C₁₋₅straight chain alkylene)R₁₅; wherein R₁₅ is H,C₁₋₇alkyl, [di(C₁₋₂alkyl)amino](C₁₋₆alkylene)-,(C₁₋₃alkoxyacyl)(C₁₋₆alkylene)-, C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl;wherein R₄ has no more than 9 carbon atoms; alternatively, R₄ is-(straight chain C₁₋₅alkylene)R₁₆; wherein R₁₆ is C₃₋₆cycloalkyl or a5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatomsselected from N, O, and S; wherein each of the above hydrocarbyl andheterocarbyl moieties may be optionally substituted with between 1 and 3substituents independently selected from F, Cl, Br, I, amino, methyl,ethyl, hydroxy or methoxy; comprising

reacting a compound of formula (III), to yield the correspondingcompound of formula (IV), wherein Pg¹ is a nitrogen protecting groupwhich is inert to ClSO₃H;

reacting the compound of formula (IV) with ClSO₃H, to yield thecorresponding compound of formula (VIIa);

reacting the compound of formula (VIIa) with a reducing agent capable ofreducing the chlorosulfonyl group on the compound of formula (VIIa), toyield a mixture of the corresponding compound of formula (VIIIa) and thecorresponding compound of formula (IXa);

de-protecting the compound of formula (VIIIa), isolated or in a mixturewith the compound of formula (IXa), to yield the corresponding compoundof formula (XIIIa); and then reacting the compound of formula (XIIIa)with a suitably substituted compound of formula (X), wherein W is Cl, Bror I, in the presence of a base, to yield the corresponding compound offormula (La); alternatively, reacting the compound of formula (IXa),isolated or in a mixture with the compound of formula (VIIIa), with areducing agent capable of reducing the disulfide on the compound offormula (IXa), to yield the corresponding compound of formula (VIIIa);then reacting the compound of formula (VIIIa) with a suitablysubstituted compound of formula (X) wherein W is Br, Cl or I, in thepresence of a base, to yield the corresponding compound of formula(XIa); and then reacting the compound of formula (XIa), to yield thecorresponding compound of formula (La); alternatively still,de-protecting the compound of formula (IXa), isolated or in a mixturewith the compound of formula (VIIIa), to yield the correspondingcompound of formula (XIIa); then reacting the compound of formula (XIIa)with a reducing agent capable of reducing the disulfide on the compoundof formula (XIIa), to yield the corresponding compound of formula (XIa);and then reacting the compound of formula (XIIIa) with a suitablysubstituted compound of formula (X) wherein W is Br, Cl or I, in thepresence of a base, to yield the corresponding compound of formula (La);

reacting the compound of formula (La) with a suitably substitutedcompound of formula (V) wherein R_(4a) is R₄ other than hydrogen andwherein J is Br, Cl or I, to yield the corresponding compound of formula(Lb); alternatively, reacting the compound of formula (La) with asuitably substituted acylating agent capable of attaching an—C(O)—R_(4b) group onto the nitrogen of the compound of formula (La),wherein R_(4b) is selected from (C₁₋₄ straight chain alkylene)R₁₅ or(straight chain C₁₋₄alkylene)R₁₆, in the presence of a base, to yieldthe corresponding compound of formula (XVIII); and then reacting thecompound of formula (XVIII) with a reducing agent capable of reducingthe amide on the compound of formula (XVIII), to yield the correspondingcompound of formula (Lb).
 14. A process for the preparation of acompound of formula (I)

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆ amide thereof,wherein each of R₁ and R₂ is independently H, C₁₋₆alkyl,(CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or (CH₂)_(m)CO₂R₈;wherein each of R_(a), R_(b), and R₈ is independently H or C₁₋₆alkyl;and m is an integer from 1 to 6; alternatively, R₁ and R₂ are takentogether with the carbon atom to which they are attached to form aC₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; provided that whenn is 1, X is bound at the 5 or 6 position; and when n is 2, X is boundat the 6 or 7 position; provided further that when n is 2 and X is boundat the 6 position, then R³ is other than hydrogen and bound at the 7position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X; provided thatR₃ is other than CF₃; each R₉ and R₁₀ is independently C₁₋₆alkyl; R₄ isH or —(C₁₋₅straight chain alkylene)R₁₅; wherein R₁₅ is H, C₁₋₇alkyl,[di(C₁₋₂alkyl)amino](C₁₋₆alkylene)-, (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)-,C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl; wherein R₄ has no more than 9carbon atoms; alternatively, R₄ is -(straight chain C₁₋₅alkylene)R₁₆;wherein R₁₆ is C₃₋₆cycloalkyl or a 5-6 membered non-aromaticheterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;c is an integer from 0 to 1; each of R₅ and R₇ is independently selectedfrom H, C₁₋₆alkyl, halo, cyano, nitro, COR₁₁, COOR₁₁, C₁₋₄alkoxy,C₁₋₄alkylthio, hydroxy, phenyl, NR₁₁R₁₂ or a 5-6 membered heterocyclylwith between 1 and 2 heteroatoms selected from N, O, and S; R₆ isselected from C₁₋₆alkyl, halo, cyano, nitro, COR₁₃, COOR₁₃, C₁₋₄alkoxy,C₁₋₄alkylthio, hydroxy, phenyl, NR₁₃R₁₄ or a 5-6 membered heterocyclylwith between 1 and 2 heteroatoms selected from N, O, and S;alternatively, R₅ and R₆ or R₆ and R₇ may be taken together to be abivalent moiety, saturated or unsaturated, selected from C₃₋₄alkylene,C₃₋₄alkenylene or (CH₁₋₂)_(p)N(CH₁₋₂)_(q); p is an integer from 0 to 2and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;each R₁₁, R₁₂, R₁₃ and R₁₄ is independently H or C₁₋₆alkyl; wherein eachof the above hydrocarbyl and heterocarbyl moieties may be optionallysubstituted with between 1 and 3 substituents independently selectedfrom F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy; comprisingthe process of claim 13 and further comprising

reacting the compound of formula (L), to yield the correspondingcompound of formula (I).
 15. A process for the preparation of a compoundof formula (I)

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆ amide thereof,wherein each of R₁ and R₂ is independently H, C₁₋₆alkyl,(CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or (CH₂)_(m)CO₂R₈;wherein each of R_(a), R_(b), and R₈ is independently H or C₁₋₆alkyl;and m is an integer from 1 to 6; alternatively, R₁ and R₂ are takentogether with the carbon atom to which they are attached to form aC₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; provided that whenn is 1, X is bound at the 5 or 6 position; and when n is 2, X is boundat the 6 or 7 position; provided further that when n is 2 and X is boundat the 6 position, then R³ is other than hydrogen and bound at the 7position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X; provided thatR₃ is other than CF₃; each R₉ and R₁₀ is independently C₁₋₆alkyl; R₄ isH or —(C₁₋₅straight chain alkylene)R₁₅; wherein R₁₅ is H, C₁₋₇alkyl,[di(C₁₋₂alkyl)amino](C₁₋₆alkylene)-, (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)-,C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl; wherein R₄ has no more than 9carbon atoms; alternatively, R₄ is -(straight chain C₁₋₅alkylene)R₁₆;wherein R₁₆ is C₃₋₆cycloalkyl or a 5-6 membered non-aromaticheterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;c is an integer from 0 to 1; each of R₅ and R₇ is independently selectedfrom H, C₁₋₆alkyl, halo, cyano, nitro, COR₁₁, COOR₁₁, C₁₋₄alkoxy,C₁₋₄alkylthio, hydroxy, phenyl, NR₁₁R₁₂ or a 5-6 membered heterocyclylwith between 1 and 2 heteroatoms selected from N, O, and S; R₆ isselected from C₁₋₆alkyl, halo, cyano, nitro, COR₁₃, COOR₁₃, C₁₋₄alkoxy,C₁₋₄alkylthio, hydroxy, phenyl, NR₁₃R₁₄ or a 5-6 membered heterocyclylwith between 1 and 2 heteroatoms selected from N, O, and S;alternatively, R₅ and R₆ or R₆ and R₇ may be taken together to be abivalent moiety, saturated or unsaturated, selected from C₃₋₄alkylene,C₃₋₄alkenylene or (CH₁₋₂)_(p)N(CH₁₋₂)_(q); p is an integer from 0 to 2and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;each R₁₁, R₁₂, R₁₃ and R₁₄ is independently H or C₁₋₆alkyl; wherein eachof the above hydrocarbyl and heterocarbyl moieties may be optionallysubstituted with between 1 and 3 substituents independently selectedfrom F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy; comprising

reacting a compound of formula (III), to yield the correspondingcompound of formula (IV), wherein Pg¹ is a nitrogen protecting groupwhich is inert to ClSO₃H;

reacting the compound of formula (IV) with ClSO₃H, to yield thecorresponding compound of formula (VIIa);

reacting the compound of formula (VIIa) with a reducing agent capable ofreducing the chlorosulfonyl group on the compound of formula (VIIa), toyield a mixture of the corresponding compound of formula (VIIIa) and thecorresponding compound of formula (IXa);

de-protecting the compound of formula (VIIIa), isolated or in a mixturewith the compound of formula (IXa), to yield the corresponding compoundof formula (XIIIa); and then reacting the compound of formula (XIIIa)with a suitably substituted compound of formula (X), wherein Q isselected from the group consisting of OH, OPg², NH₂ and N(Pg³Pg⁴);wherein Pg² is a carboxylic acid protecting group; and wherein Pg³ andPg⁴ are each independently selected from hydrogen, C₁₋₈alkyl,C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are taken together with thenitrogen atom to which they are bound to form C₃₋₁₀heteroaryl orC₃₋₁₀non-aromatic heterocyclic; and wherein W is Br, Cl or I; in thepresence of a base, to yield the corresponding compound of formula (La);alternatively, reacting the compound of formula (IXa), isolated or in amixture with the compound of formula (VIIIa), with a reducing agentcapable of reducing the disulfide on the compound of formula (IXa), toyield the corresponding compound of formula (VIIIa); then reacting thecompound of formula (VIIIa) with a suitably substituted compound offormula (X) wherein Q is selected from the group consisting of OH, OPg²,NH₂ and N(Pg³Pg⁴); wherein Pg² is a carboxylic acid protecting group;and wherein Pg³ and Pg⁴ are each independently selected from hydrogen,C₁₋₈alkyl, C₃₋₈Cycloalkyl or aryl; or Pg³ and Pg⁴ are taken togetherwith the nitrogen atom to which they are bound to form C₃₋₁₀heteroarylor C₃₋₁₀non-aromatic heterocyclic; and wherein W is Br, Cl or I; in thepresence of a base, to yield the corresponding compound of formula(XIa); and then reacting the compound of formula (XIa), to yield thecorresponding compound of formula (La); alternatively still,de-protecting the compound of formula (IXa), isolated or in a mixturewith the compound of formula (VIIIa), to yield the correspondingcompound of formula (XIIa); then reacting the compound of formula (XIIa)with a reducing agent capable of reducing the disulfide on the compoundof formula (XIIa), to yield the corresponding compound of formula(XIIIa); and then reacting the compound of formula (XIIIa) with asuitably substituted compound of formula (X), wherein Q is selected fromthe group consisting of OH, OPg², NH₂ and N(Pg³Pg⁴); wherein Pg² is acarboxylic acid protecting group; and wherein Pg³ and Pg⁴ are eachindependently selected from hydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl;or Pg³ and Pg⁴ are taken together with the nitrogen atom to which theyare bound to form C₃₋₁₀heteroaryl or C₃₋₁₀non-aromatic heterocyclic; andwherein W is Br, Cl or I; in the presence of a base, to yield thecorresponding compound of formula (La);

reacting the compound of formula (La) with a suitably substitutedcompound of formula (V), wherein R_(4a) is R₄ other than hydrogen andwherein J is Br, Cl or I, to yield the corresponding compound of formula(Lb); alternatively, reacting the compound of formula (La) with asuitably substituted acylating agent capable of attaching an—C(O)—R_(4b) group onto the nitrogen of the compound of formula (La),wherein R_(4b) is selected from (C₁₋₄ straight chain alkylene)R₁₅ or(straight chain C₁₋₄alkylene)R₁₆, in the presence of a base, to yieldthe corresponding compound of formula (XVIII); and then reacting thecompound of formula (XVIII) with a reducing agent capable of reducingthe amide on the compound of formula (XVIII), to yield the correspondingcompound of formula (Lb);

reacting the compound of formula (La) or the compound of formula (Lb),to yield the corresponding compound of formula (I).
 16. The process ofclaim 13 wherein Q is OPg², Pg² is t-butyl, X is S, R₁ is methyl, R₂ ismethyl, the —X—C(R₁R₂)—C(O)-Q group is bound at the 5-position, R₃ ishydrogen, n is 1 and R₄ is ethyl.
 17. The process of claim 14 wherein Xis S, R₁ is methyl, R₂ is methyl, the —X—C(R₁R₂)—C(O)—OH group is boundat the 5-position, R₃ is hydrogen, n is 1, R₄ is ethyl, c is 0, R₅ ishydrogen, R₆ is trifluoromethoxy and R₇ is hydrogen.
 18. The process ofclaim 15 wherein X is S, R₁ is methyl, R₂ is methyl, the—X—C(R₁R₂)—C(O)—OH group is bound at the 5-position, R₃ is hydrogen, nis 1, R₄ is ethyl, c is 0, R₅ is hydrogen, R₆ is trifluoromethoxy and R₇is hydrogen.
 19. A process for the preparation of a compound of formula(Lc)

wherein Q is selected from the group consisting of OH, OPg², NH₂ andN(Pg³Pg⁴); wherein Pg² is a carboxylic acid protecting group; andwherein Pg³ and Pg⁴ are each independently selected from hydrogen,C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are taken togetherwith the nitrogen atom to which they are bound to form C₃₋₁₀heteroarylor C₃₋₁₀non-aromatic heterocyclic; each of R₁ and R₂ is independently H,C₁₋₆alkyl, (CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or(CH₂)_(m)CO₂R₈; wherein each of R_(a), R_(b), and R₈ is independently Hor C₁₋₆alkyl; and m is an integer from 1 to 6; alternatively, R₁ and R₂are taken together with the carbon atom to which they are attached toform a C₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; providedthat when n is 1, X is bound at the 5 or 6 position; and when n is 2, Xis bound at the 6 or 7 position; provided further that when n is 2 and Xis bound at the 6 position, then R³ is other than hydrogen and bound atthe 7 position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl,NR₉R₁₀, NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X;provided that R₃ is other than CF₃; each R₉ and R₁₀ is independentlyC₁₋₆alkyl; R_(4b) is —(C₁₋₄straight chain alkylene)R₁₅; wherein R₁₅ isH, C₁₋₇alkyl, [di(C₁₋₂alkyl)amino](C₁₋₆alkylene)-,(C₁₋₃alkoxyacyl)(C₁₋₆alkylene)-, C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl;wherein R_(4b) has no more than 8 carbon atoms; alternatively, R_(4b) is-(straight chain C₁₋₄alkylene)R₁₆; wherein R₁₆ is C₃₋₆cycloalkyl or a5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatomsselected from N, O, and S; wherein each of the above hydrocarbyl andheterocarbyl moieties may be optionally substituted with between 1 and 3substituents independently selected from F, Cl, Br, I, amino, methyl,ethyl, hydroxy or methoxy; comprising

reacting a suitably substituted compound of formula (III) with asuitably substituted acylating agent capable of attaching an—C(O)—R_(4b) group onto the nitrogen of the compound of formula (III),in the presence of a base, to yield the corresponding compound offormula (XIV);

reacting the compound of formula (XIV) with ClSO₃H, to yield thecorresponding compound of formula (XV);

reacting the compound of formula (XV) with a reducing agent capable ofreducing the chlorosulfonyl group on the compound of formula (XV), toyield a mixture of the corresponding compound of formula (XVI) and thecorresponding compound of formula (XVII);

reacting the compound of formula (XVI), isolated or in a mixture withthe compound of formula (XVII), with a reducing agent capable ofreducing the amide on the compound of formula (XVI), to yield thecorresponding compound of formula (XIIIb); alternatively, reacting thecompound of formula (XVII), isolated or in a mixture with the compoundof formula (XVI), with a reducing agent capable of reducing the amideand the disulfide on the compound of formula (XVII), to yield thecorresponding compound of formula (XIIIb);

reacting the compound of formula (XIIIb) with a suitably substitutedcompound of formula (X) wherein W is Br, Cl or I, in the presence of abase, to yield the corresponding compound of formula (Lc).
 20. A processfor the preparation of a compound of formula (Ic)

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆ amide thereof,wherein each of R₁ and R₂ is independently H, C₁₋₆alkyl,(CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or (CH₂)_(m)CO₂R₈;wherein each of R_(a), R_(b), and R₈ is independently H or C₁₋₆alkyl;and m is an integer from 1 to 6; alternatively, R₁ and R₂ are takentogether with the carbon atom to which they are attached to form aC₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; provided that whenn is 1, X is bound at the 5 or 6 position; and when n is 2, X is boundat the 6 or 7 position; provided further that when n is 2 and X is boundat the 6 position, then R³ is other than hydrogen and bound at the 7position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X; provided thatR₃ is other than CF₃; each R₉ and R₁₀ is independently C₁₋₆alkyl; R_(4b)is —(C₁₋₄straight chain alkylene)R₁₅; wherein R₁₅ is H, C₁₋₇alkyl,[di(C₁₋₂alkyl)amino](C₁₋₆alkylene)-, (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)-,C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl; wherein R_(4b) has no more than8 carbon atoms; alternatively, R_(4b) is -(straight chainC₁₋₄alkylene)R₁₆; wherein R₁₆ is C₃₋₆cycloalkyl or a 5-6 memberednon-aromatic heterocyclyl with between 1 and 2 heteroatoms selected fromN, O, and S; c is an integer from 0 to 1; each of R₅ and R₇ isindependently selected from H, C₁₋₆alkyl, halo, cyano, nitro, COR₁₁,COOR₁₁, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, phenyl, NR₁₁R₁₋₂ or a 5-6membered heterocyclyl with between 1 and 2 heteroatoms selected from N,O, and S; R₆ is selected from C₁₋₆alkyl, halo, cyano, nitro, COR₁₃,COOR₁₃, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, phenyl, NR₁₃R₁₄ or a 5-6membered heterocyclyl with between 1 and 2 heteroatoms selected from N,O, and S; alternatively, R₅ and R₆ or R₆ and R₇ may be taken together tobe a bivalent moiety, saturated or unsaturated, selected fromC₃₋₄alkylene, C₃₋₄alkenylene or (CH₁₋₂)_(p)N(CH₁₋₂)_(q); p is an integerfrom 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is atleast 2; each R₁₁, R₁₂, R₁₃ and R₁₄ is independently H or C₁₋₆alkyl;wherein each of the above hydrocarbyl and heterocarbyl moieties may beoptionally substituted with between 1 and 3 substituents independentlyselected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;comprising the process of claim 19 and further comprising

reacting the compound of formula (Lc), to yield the correspondingcompound of formula (Ic).
 21. A process for the preparation of acompound of formula (I)

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆ amide thereof,wherein each of R₁ and R₂ is independently H, C₁₋₆alkyl,(CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or (CH₂)_(m)CO₂R₈;wherein each of R_(a), R_(b), and R₈ is independently H or C₁₋₆alkyl;and m is an integer from 1 to 6; alternatively, R₁ and R₂ are takentogether with the carbon atom to which they are attached to form aC₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; provided that whenn is 1, X is bound at the 5 or 6 position; and when n is 2, X is boundat the 6 or 7 position; provided further that when n is 2 and X is boundat the 6 position, then R³ is other than hydrogen and bound at the 7position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X; provided thatR₃ is other than CF₃; each R₉ and R₁₀ is independently C₁₋₆alkyl; R_(4b)is —(C₁₋₄straight chain alkylene)R₁₅; wherein R₁₅ is H, C₁₋₇alkyl,[di(C₁₋₂alkyl)amino](C₁₋₆alkylene)-, (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)-,C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl; wherein R_(4b) has no more than8 carbon atoms; alternatively, R_(4b) is -(straight chainC₁₋₄alkylene)R₁₆; wherein R₁₆ is C₃₋₆cycloalkyl or a 5-6 memberednon-aromatic heterocyclyl with between 1 and 2 heteroatoms selected fromN, O, and S; c is an integer from 0 to 1; each of R₅ and R₇ isindependently selected from H, C₁₋₆alkyl, halo, cyano, nitro, COR₁₁,COOR₁₁, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, phenyl, NR₁₁R₁₂ or a 5-6membered heterocyclyl with between 1 and 2 heteroatoms selected from N,O, and S; R₆ is selected from C₁₋₆alkyl, halo, cyano, nitro, COR₁₃,COOR₁₃, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, phenyl, NR₁₃R₁₄ or a 5-6membered heterocyclyl with between 1 and 2 heteroatoms selected from N,O, and S; alternatively, R₅ and R₆ or R₆ and R₇ may be taken together tobe a bivalent moiety, saturated or unsaturated, selected fromC₃₋₄alkylene, C₃₋₄alkenylene or (CH₁₋₂)_(p)N(CH₁₋₂)_(q); p is an integerfrom 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is atleast 2; each R₁₁, R₁₂, R₁₃ and R₁₄ is independently H or C₁₋₆alkyl;wherein each of the above hydrocarbyl and heterocarbyl moieties may beoptionally substituted with between 1 and 3 substituents independentlyselected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;comprising

reacting a suitably substituted compound of formula (III) with asuitably substituted acylating agent capable of attaching an—C(O)—R_(4b) group onto the nitrogen of the compound of formula (III),in the presence of a base, to yield the corresponding compound offormula (XIV);

reacting the compound of formula (XIV) with ClSO₃H, to yield thecorresponding compound of formula (XV);

reacting the compound of formula (XV) with a reducing agent capable ofreducing the chlorosulfonyl group on the compound of formula (XV), toyield a mixture of the corresponding compound of formula (XVI) and thecorresponding compound of formula (XVII);

reacting the compound of formula (XVI), isolated or in a mixture withthe compound of formula (XVII), with a reducing agent capable ofreducing the amide on the compound of formula (XVI), to yield thecorresponding compound of formula (XIIIb); alternatively, reacting thecompound of formula (XVII), isolated or in a mixture with the compoundof formula (XVI), with a reducing agent capable of reducing the amideand the disulfide on the compound of formula (XVII), to yield thecorresponding compound of formula (XIIIb);

reacting the compound of formula (XIIIb) with a suitably substitutedcompound of formula (X) wherein Q is selected from the group consistingof OH, OPg², NH₂ and N(Pg³Pg⁴); wherein Pg² is a carboxylic acidprotecting group; and wherein Pg³ and Pg⁴ are each independentlyselected from hydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ andPg⁴ are taken together with the nitrogen atom to which they are bound toform C₃loheteroaryl or C₃₋₁₀non-aromatic heterocyclic; and W is Br, Clor I; in the presence of a base, to yield the corresponding compound offormula (Lc);

reacting the compound of formula (Lc), to yield the correspondingcompound of formula (Ic).
 22. The process of claim 19 wherein Q is Opg²,Pg² is t-butyl, X is S, R₁ is methyl, R₂ is methyl, wherein the—X—C(R₁R₂)—C(O)Q group is bound at the 5-position, R₃ is hydrogen, n is1 and R₄ is ethyl
 23. The process of claim 20 wherein X is S, R₁ ismethyl, R₂ is methyl, the-X—C(R₁R₂)—C(O)—OH group is bound at the5-position, R₃ is hydrogen, n is 1, R₄ is ethyl, c is 0, R₅ is hydrogen,R₆ is trifluoromethoxy and R₇ is hydrogen.
 24. The process of claim 21wherein X is S, R₁ is methyl, R₂ is methyl, the-X—C(R₁R₂)—C(O)—OH groupis bound at the 5-position, R₃ is hydrogen, n is 1, R₄ is ethyl, c is 0,R₅ is hydrogen, R₆ is trifluoromethoxy and R₇ is hydrogen.
 25. A processfor the preparation of a compound of formula (Lc)

wherein Q is selected from the group consisting of OH, OPg², NH₂ andN(Pg³Pg⁴); wherein Pg² is a carboxylic acid protecting group; andwherein Pg³ and Pg⁴ are each independently selected from hydrogen,C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ and Pg⁴ are taken togetherwith the nitrogen atom to which they are bound to form C₃₋₁₀heteroarylor C₃₋₁₀non-aromatic heterocyclic; each of R₁ and R₂ is independently H,C₁₋₆alkyl, (CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or(CH₂)_(m)CO₂R₈; wherein each of R_(a), R_(b), and R₈ is independently Hor C₁₋₆alkyl; and m is an integer from 1 to 6; alternatively, R₁ and R₂are taken together with the carbon atom to which they are attached toform a C₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; providedthat when n is 1, X is bound at the 5 or 6 position; and when n is 2, Xis bound at the 6 or 7 position; provided further that when n is 2 and Xis bound at the 6 position, then R³ is other than hydrogen and bound atthe 7 position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl,NR₉R₁₀, NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X;provided that R₃ is other than CF₃; each R₉ and R₁₀ is independentlyC₁₋₆alkyl; R_(4b) is —(C₁₋₄straight chain alkylene)R₁₅; wherein R₁₅ isH, C₁₋₇alkyl, [di(C₁₋₂alkyl)amino](C₁₋₆alkylene)-,(C₁₋₃alkoxyacyl)(C₁₋₆alkylene)-, C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl;wherein R_(4b) has no more than 8 carbon atoms; alternatively, R_(4b) is-(straight chain C₁₋₄alkylene)R₁₆; wherein R₁₆ is C₃₋₆cycloalkyl or a5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatomsselected from N, O, and S; wherein each of the above hydrocarbyl andheterocarbyl moieties may be optionally substituted with between 1 and 3substituents independently selected from F, Cl, Br, I, amino, methyl,ethyl, hydroxy or methoxy; comprising

reacting a suitably substituted compound of formula (III) with asuitably substituted acylating agent capable of attaching an—C(O)—R_(4b) group onto the nitrogen of the compound of formula (III),in the presence of a base, to yield the corresponding compound offormula (XIV);

reacting the compound of formula (XIV) with ClSO₃H, to yield thecorresponding compound of formula (XV);

reacting the compound of formula (XV) with a reducing agent capable ofreducing the chlorosulfonyl group and the amide group on the compound offormula (XV), to yield the corresponding compound of formula (XIIIb);

reacting the compound of formula (XIIIb) with a suitably substitutedcompound of formula (X) wherein W is Br, Cl or I, in the presence of abase, to yield the corresponding compound of formula (Lc).
 26. A processfor the preparation of a compound of formula (Ic)

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆ amide thereof,wherein each of R₁ and R₂ is independently H, C₁₋₆alkyl,(CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or (CH₂)_(m)CO₂R₈;wherein each of R_(a), R_(b), and R₈ is independently H or C₁₋₆alkyl;and m is an integer from 1 to 6; alternatively, R₁ and R₂ are takentogether with the carbon atom to which they are attached to form aC₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; provided that whenn is 1, X is bound at the 5 or 6 position; and when n is 2, X is boundat the 6 or 7 position; provided further that when n is 2 and X is boundat the 6 position, then R³ is other than hydrogen and bound at the 7position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X; provided thatR₃ is other than CF₃; each R₉ and R₁₀ is independently C₁₋₆alkyl; R_(4b)is —(C₁₋₄straight chain alkylene)R₁₅; wherein R₁₅ is H, C₁₋₇alkyl,[di(C₁₋₂alkyl)amino](C₁₋₆alkylene)-, (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)-,C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl; wherein R_(4b) has no more than8 carbon atoms; alternatively, R_(4b) is -(straight chainC₁₋₄alkylene)R₁₆; wherein R₁₆ is C₃₋₆cycloalkyl or a 5-6 memberednon-aromatic heterocyclyl with between 1 and 2 heteroatoms selected fromN, O, and S; c is an integer from 0 to 1; each of R₅and R₇ isindependently selected from H, C₁₋₆alkyl, halo, cyano, nitro, COR₁₁,COOR₁₁, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, phenyl, NR₁₁R₁₂ or a 5-6membered heterocyclyl with between 1 and 2 heteroatoms selected from N,O, and S; R₆ is selected from C₁₋₆alkyl, halo, cyano, nitro, COR₁₃,COOR₁₃, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, phenyl, NR₁₃R₁₄ or a 5-6membered heterocyclyl with between 1 and 2 heteroatoms selected from N,O, and S; alternatively, R₅ and R₆ or R₆ and R₇ may be taken together tobe a bivalent moiety, saturated or unsaturated, selected fromC₃₋₄alkylene, C₃₋₄alkenylene or (CH₁₋₂)_(p)N(CH₁₋₂)_(q); p is an integerfrom 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is atleast 2; each R₁₁, R₁₂, R₁₃ and R₁₄ is independently H or C₁₋₆alkyl;wherein each of the above hydrocarbyl and heterocarbyl moieties may beoptionally substituted with between 1 and 3 substituents independentlyselected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;comprising the process of claim 25 and further comprising

reacting the compound of formula (Lc), to yield the correspondingcompound of formula (Ic).
 27. A process for the preparation of acompound of formula (I)

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆ amide thereof,wherein each of R₁ and R₂ is independently H, C₁₋₆alkyl,(CH₂)_(m)NR_(a)R_(b), (CH₂)_(m)OR₈, (CH₂)_(m)NH(CO)R₈ or (CH₂)_(m)CO₂R₈;wherein each of R_(a), R_(b), and R₈ is independently H or C₁₋₆alkyl;and m is an integer from 1 to 6; alternatively, R₁ and R₂ are takentogether with the carbon atom to which theyare attached to form aC₃₋₇cycloalkyl; n is an integer from 1 to 2; X is S; provided that whenn is 1, X is bound at the 5 or 6 position; and when n is 2, X is boundat the 6 or 7 position; provided further that when n is 2 and X is boundat the 6 position, then R³ is other than hydrogen and bound at the 7position; R₃ is H, C₁₋₃alkoxy, C₁₋₃alkylthio, halo, C₁₋₆alkyl, NR₉R₁₀,NHCOR₁₀, CONHR₁₀ or COOR₁₀; and R₃ is ortho or meta to X; provided thatR₃ is other than CF₃; each R₉ and R₁₀ is independently C₁₋₆alkyl; R_(4b)is —(C₁₋₄straight chain alkylene)R₁₅; wherein R₁₅ is H, C₁₋₇alkyl,[di(C₁₋₂alkyl)amino](C₁₋₆alkylene)-, (C₁₋₃alkoxyacyl)(C₁₋₆alkylene)-,C₁₋₆alkoxy, C₃₋₇alkenyl or C₃₋₈alkynyl; wherein R_(4b) has no more than8 carbon atoms; alternatively, R_(4b) is -(straight chainC₁₋₄alkylene)R₁₆; wherein R₁₋₆ is C₃₋₆cycloalkyl or a 5-6 memberednon-aromatic heterocyclyl with between 1 and 2 heteroatoms selected fromN, O, and S; c is an integer from 0 to 1; each of R₅ and R₇ isindependently selected from H, C₁₋₆alkyl, halo, cyano, nitro, COR₁₁,COOR₁₁, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, phenyl, NR₁₁R₁₂ or a 5-6membered heterocyclyl with between 1 and 2 heteroatoms selected from N,O, and S; R₆ is selected from C₁₋₆alkyl, halo, cyano, nitro, COR₁₃,COOR₁₃, C₁₋₄alkoxy, C₁₋₄alkylthio, hydroxy, phenyl, NR₁₃R₁₄ or a 5-6membered heterocyclyl with between 1 and 2 heteroatoms selected from N,O, and S; alternatively, R₅ and R₆ or R₆ and R₇ may be taken together tobe a bivalent moiety, saturated or unsaturated, selected fromC₃₋₄alkylene, C₃₋₄alkenylene or (CH₁₋₂)_(p)N(CH₁₋₂)_(q); p is an integerfrom 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is atleast 2; each R₁₁, R₁₂, R₁₃ and R₁₄ is independently H or C₁₋₆alkyl;wherein each of the above hydrocarbyl and heterocarbyl moieties may beoptionally substituted with between 1 and 3 substituents independentlyselected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;comprising

reacting a suitably substituted compound of formula (III) with asuitably substituted acylating agent capable of attaching an—C(O)—R_(4b) group onto the nitrogen of the compound of formula (III),in the presence of a base, to yield the corresponding compound offormula (XIV);

reacting the compound of formula (XIV) with ClSO₃H, to yield thecorresponding compound of formula (XV);

reacting the compound of formula (XV) with a reducing agent capable ofreducing the chlorosulfonyl group and the amide group on the compound offormula (XV), to yield the corresponding compound of formula (XIIIb);

reacting the compound of formula (XIIIb) with a suitably substitutedcompound of formula (X) wherein Q is selected from the group consistingof OH, OPg², NH₂ and N(Pg³Pg⁴); wherein Pg² is a carboxylic acidprotecting group; and wherein Pg³ and Pg⁴ are each independentlyselected from hydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl or aryl; or Pg³ andPg⁴ are taken together with the nitrogen atom to which they are bound toform C₃₋₁₀heteroaryl or C₃₋₁₀non-aromatic heterocyclic; and W is Br, Clor I; in the presence of a base, to yield the corresponding compound offormula (Lc);

reacting the compound of formula (Lc), to yield the correspondingcompound of formula (Ic).
 28. The process of claim 25 wherein Q is OPg²,Pg² is t-butyl, X is S, R₁ is methyl, R₂ is methyl, wherein the—X—C(R₁R₂)—C(O)Q group is bound at the 5-position, R₃ is hydrogen, n is1 and R₄ is ethyl
 29. The process of claim 26 wherein X is S, R₁ ismethyl, R₂ is methyl, the-X—C(R₁R₂)—C(O)—OH group is bound at the5-position, R₃ is hydrogen, n is 1, R₄ is ethyl, c is 0, R₅ is hydrogen,R₆ is trifluoromethoxy and R₇ is hydrogen.
 30. The process of claim 27wherein X is S, R₁ is methyl, R₂ is methyl, the-X—C(R₁R₂)—C(O)—OH groupis bound at the 5-position, R₃ is hydrogen, n is 1, R₄ is ethyl, c is 0,R₅ is hydrogen, R₆ is trifluoromethoxy and R₇ is hydrogen.
 31. A processfor the preparation of a compound of formula (Le)

wherein Q_(b) is selected from the group consisting of C₁₋₆alkoxy,wherein the C₁₋₆alkoxy is not substituted with amino; comprising

(a) reacting a compound of formula (Ld) with(S)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, ata temperature in the range of from about 35° C. to about 0° C.; to yieldthe corresponding (R,S) diastereomeric salt, the compound of formula(XX);

(b) reacting the (R,S) diastereomeric salt, the compound of formula(XX), with an inorganic base, to yield the corresponding compound offormula (Le).
 32. The process of claim 31 wherein Q_(b) is t-butoxy. 33.A process for the preparation of a compound of formula (Le)

wherein Q_(b) is selected from the group consisting of C₁₋₆alkoxy,wherein the C₁₋₆alkoxy is not substituted with amino; comprising

(a) reacting a compound of formula (Ld) with(R)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperaturegreater than about 35° C.; or in THF at about room temperature; to yieldthe corresponding (R,R) diastereomeric salt, the compound of formula(XXI);

(b) reacting the (R,R) diastereomeric salt, the compound of formula(XXI) with an inorganic base, to yield the corresponding compound offormula (Le).
 34. The process of claim 33 wherein Q_(b) is t-butoxy. 35.A process for the preparation of the compound of formula (Lf)

wherein Q_(b) is selected from the group consisting of C₁₋₆alkoxy,wherein the C₁₋₆alkoxy is not substituted with amino; comprising

(a) reacting a compound of formula (Ld) with(S)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperaturegreater than about 35° C.; or in THF at about room temperature; to yieldthe corresponding (S,S) diastereomeric salt, the compound of formula(XXII);

(b) reacting the (S,S) diastereomeric salt, the compound of formula(XXI) with an inorganic base, to yield the corresponding compound offormula (Lf).
 36. A process for the preparation of the compound offormula (Lf)

wherein Q_(b) is selected from the group consisting of C₁₋₆alkoxy,wherein the C₁₋₆alkoxy is not substituted with amino; comprising

(a) reacting a compound of formula (Ld) with(R)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, ata temperature in the range of from about 35° C. to about 0° C.; to yieldthe corresponding (S,R) diastereomeric salt, the compound of formula(XXIII);

(b) reacting the (S,R) diastereomeric salt, the compound of formula(XXIII) with an inorganic base, to yield the corresponding compound offormula (Lf).
 37. A crystalline N,N′-dibenzylethylenediamine salt of acompound of formula (IIa)


38. The crystalline salt as in claim 37 wherein the ratio of thecompound of formula (IIa) to the N,N′-dibenzylethylenediamine is 1:1.39. A crystalline N,N′-dibenzylethylenediamine salt of a compound offormula (IIa)

comprising the following X-ray diffraction peaks: Position [°2θ]d-spacing [Å] Relative Intensity [%] 6.3894 13.8336 17.39 8.0423 10.993813.38 12.157 7.2803 19.22 16.012 5.5354 15.74 17.929 4.9475 20.77 18.0484.9151 14.20 19.038 4.6618 100.00 19.2656 4.6072 26.28 20.325 4.369410.65 21.943 4.0508 16.85 22.190 4.0063 18.63 22.330 3.9815 12.37


40. A process for the preparation of a N,N′-dibenzylethylenediamine saltof a compound of formula (IIa)


41. The process of claim 40 wherein the aprotic solvent is isopropylalcohol.
 42. The process of claim 41 wherein the compound of formula(IIa) is reacted with N,N′-dibenzylethylenediaine at a temperature lessthan about 5° C.
 43. A compound of formula (IIa) comprising thestructure:

or a pharmaceutically acceptable salt, C₁₋₆ ester or C₁₋₆ amide thereof.44. The compound of claim 43 wherein said compound has an enantiomericexcess of at least about 90% .
 45. The compound of claim 43 wherein saidcompound has an enantiomeric excess of at least about 96% .
 46. Thecompound of claim 43 wherein said compound has an enantiomeric excess ofat least about 99% .
 47. A compound comprising the structure:


48. The comnpound of claim 47 wherein said compound has an enantiomericexcess of at least about 90% .
 49. The compound of claim 47 wherein saidcompound has an enantiomeric excess of at least about 96% .
 50. Thecompound of claim 47 wherein said compound has an enantiomeric excess ofat least about 99% .
 51. A pharmaceutical composition comprising thecompound of claim
 43. 52. A pharmaceutical composition comprising thecompound of claim 47.